4, 6-pregnadieno-[3, 2-c] pyrazoles and processes of preparing them



United States Patent ()fitice 3,667,194 Patented Dec. 4, 1952 3,067,194 4,6-PREGNADIENO-[3,2-C] PYRAZOLES AND PROCESSES F PREPARENG THEM Max Tishier, Westfield, N.J., Nathan G. Steinherg, Brooklyn, N.Y., and Ralph F. Hirschmann, Scotch Plains, N.J., assignors to Merck & Co., Inc., Railway, N.J.,

a corporation of New Jersey N0 Drawing. Filed Dec. 1, 1961, Ser. No. 156,478 23 Claims. (Cl. 260239.5)

wherein R is fi-halogen, p-hydroxy or keto, but fl-halogen is present at R only when X is halogen, R is fluoro, hydrogen or methyl, R is hydrogen, a-methyl, flmethyl, or methylene, R is hydrogen, hydroxy, acyloxy or fiuoro, R is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or acyl and X is hydrogen or halogen, and wherein any acyl group present as an acyloxy group at K; may be the same or different from any acyl group present at R N-substitutedpyrazole compounds having structure A are herein designated as the 1-substituted-4,6-pregnadiene-[3,2-c]pyrazoles, and N-substituted-pyrazole compounds having structure B are designated as the 2'-substituted-4,6-pregnadieno-[3,2-c]pyrazoles.

The above defined 4,6-pregnadieno-[3,2-c]pyrazoles producedtin accordance with the present invention possess high anti-inflammatory activity, and are especially effective for the treatment of arthritis and related diseases since they can be administered for their cortisone-like action in low dosage thereby minimizing undesirable side elfects.

In preparing our novel chemical compounds, the starting material utilized is a 17a,21-dihydroxy-4,6-pregna- 2 diene-3,20-dione which may be identified by the follow ing structural formula:

OHrOH wherein R is fl-hydroxy or ,B-halogen, but S-halogen' is present at R only when X is halogen, R is hydrogen, fluoro or methyl, R is hydrogen, (ac-methyl, [Si-methyl or methylene, and X is hydrogen, or halogen. However, it is clear to those skilled in the art that other starting materials may be similarly converted to the desired end products.

Among the compounds which may be used as a starting material in the process of our invention are:

11B,17u,21-trihydroxy-4,6-pregnadiene-3,20-dione,

1lfi,17u-2l-trihydroxy-16a-methyl-4,-pregnadiene-3,20-

dione,

11,8,170,2l-trihydroxy-l6,B-n1ethyl-4,6-pregnadiene-3,2O-

dione,

1 1p, 17a,21-trihydroXy-1 6-methylene-4,6-pregnadiene- 3,20-dione,

l 1,6-17a,2l-trihydroXy-6-methy1-4,6-pregnadiene-3,20-

dione,

1 lfl,17a,21-trihydroXy-6,l6a-dimethyl-4,6-pregnadiene- 3,20-dione,

1l,8,l7a,21-trihydroxy-6,l6 3-dimethyl-4,G-pregnadiene- 3,20-dione,

11p,17a-21-trihydroxy-6-methyl-16-methylene-4,6-

pregnadiene-3,20-dione,

6-fiuoro-1 1B,17a,2l-trihydroXy-4,6-pregnadiene-3,20-

dione,

6-fluoro-1 1,8,17a,2l-trihydroxy-l6a-methyl-4,6-pregnadiene-3,20-dione,

6-fluoro-1 15, l7ot,21-trihydroXy-16,B-methyl-4,6-pregnadiene-3,20-dione,

6-fiuoro-1 1/3,170:,21-trihydroxy-16-methylene-4,6-

pregnadiene-3 ,20-dione,

' 9a-fluoro-11p,17a,21-trihydroxy-4,G- regnadiene-3,20-

dione,

9a-fiuoro1 1 B, 1 704,2 l-trihydroxy- 1 6a-methyl-4,6-pregnadiene-3,20-dione,

9ot-luorol 113, 17a,21-trihydroxy-16-methylene-4,6-

pregnadiene-3 ,ZO-dione,

9oc-chloro-11,8,17a,2l-trihydroxy-4,6-pregnadiene-3,20-

dione,

9a-chloro-1 1e,17u,2l-trihydroxy-16a-methyl-4,6-

pregnadiene-3,20-dione,

9u-chloro-l1,8,l7a,21-trihydroxy-16B-methyl-4,6-

pregnadiene3 ,ZO-dione,

QCt-ChlOI'O-l 1B,17a,2l-trihydroxy-l6-methylene-4,6-

pregnadiene-3,20-dione,

9oc-fiuoro-l 1 5, 1 7 (1,2 1-trihydroxy-6-methyl-4,6-pregnadiene-3 ,ZO-dione,

Qa-flUOIO-l 1B,17a,21-trihydroxy-6,16a-dimethyl-4,6-

pregnadiene-3,20-dione,

Qa-flu oro-l 1,8,17a,21-trihydroxy-6,16fi-dimethyl-4,6-

pregnadiene-3,20-dione,

9afiuOr0-l 1,8,17a,21-trihydroxy-6-methyl-16-methy1ene- 4,6-pregnadiene-3,20-dione,

9a-chloro-l 1,8, 17a,2 1-trihydroxy-6-methy1-4,6-pregnadiene-3,20-dione,

9a-chloro-11B,1700,21-trihydroxy-6,160t-dimethyl-4,6-

pregnadiene-3,20-dione,

900-chloro-1 1B,170t-21-trihydroxy-6,16B-dimethyl-4,6-

pregnadiene-3,20-dione,

900-chlro-1 1,8,170t,2l-trihydroxy-G-methyl-16-methylene- 4,6-pregnadiene-3,ZO-dione,

900-chloro11B,170t,2l-trihydroxy-6-fiuoro-4,6-

pregnadiene-3,20-dione,

6,90t-difluoro-1 1,8,17e,21-trihydroxy-4,G-pregnadiene- 3,20dione,

6,90t-difluoro-1 1,8,170:,21-trihydroxy-160t-methyl-4,6-

pregnadiene-3 ,20-dione,

6,900-difiuoro-1 1B,170:,2l-trihydroxy-16-methylene-4,6-

pregnadiene-3,20-dione,

90z-chloro-6-fiuoro-11f ,1700,21-trihydroxy-4,6-pregnadiene-3,20-dione,

90t-chloro-6-fluoro-1 1B,17a,21-trihydroxy-160t-methy1- 4,6-pregnadiene-3,20-dione,

900-chloro-6-fluor0-11B,17a,2l-trihydroxy-16fl-methy1- 4,6-pregnadiene-3,ZO-dione,

90c-chloro-6-fiuor0-l 1/3,170,21-trihydroxy-16-methy1ene- 4,6-pregnadiene-3,20-dione,

and the ll-keto analogues of the above compounds;

900,11e-dichloro-170,21-dihydroxy-4,6-pregnadiene- 3,20-dione,

900,1 lfi-dichloro-1700,21-dihydroxy-1600-methyl-4,6-

pregnadiene-3 ,ZO-dione,

90:,1lp-dichloro-170t,2l-dihydroxy-16,8-methyl-4,6-

pregnadiene-3 ,20-dione,

90L, 1 lfl-dichloro-l70t,21-dihydroxy-16-methylene-4,6-

pregnadiene-3,20-dione,

901,1 1fl-dich1or0-6-fluoro-170c,21-dihydr0Xy-4,6-pregnadiene-3,20-dione,

911,1 lfi-dichloro-G-fiuoro-170t,21-dihydroxy-160t-methyl- 4,6-pregnadiene-3,20-dione,

900,1 1fi-dichlor0-6-fiuoro-170t,21-dihydroxy-l6,8-methyl- 4,6-pregnadiene-3 ,20-dione,

90:,1 lp-dichloro-6-fluoro-1700,21-dihydIoxy-16-methylene- 4,6-pregnadiene-3 ,20-dione,

90:,1lfi-dichloro-170,2l-dihydroxy-6-rnethyl-4,6-

pregnadiene-3,20-dionc,

900,1 1 fi-dichloro- 170t,2 1-dihydroxy-6, 1 600-dirnethyl-4,6-

pregnadiene-3,20-dione,

901,1lfi-dichloro-170:,2l-dihydroxy-6,16,8,dimethy1-4,6-

pregnadiene-3 ,20-dione,

906,11 B-dlChlOrO-17d,21-dlhydfOXy-6-methy1-16-methy1- ene-4,6-pregnadiene-3 ,ZO-dione,

90c-bromo-l lfi-chloro-170z,21-dihydroxy-4,6-pregadiene- 3,20-dione,

9a-bromo-l 1,8-chloro-170t,21-dihydroxy-160t-methy1- 4,6-pregnadiene-3,20-dione,

9zx-b1'Om0-l L E-chloro-170t,21-dihydr0xy-16{3-methyl-4,6-

pregnadiene-3 ,ZO-dione,

9a-bromo-11,8-chloro-17a,2l-dihydroxy-16-methylene- 4,6-pregnadiene-3 ,20-dione,

90t-bromo-1 1fi-chloro-170!,21-dihydroxy-6fiuoro-4,6-

pregnadiene-3,20-dione,

9u-brorno-llB-chloro-170t,21-dihydroxy-6-fluoro-16umethyl-4,6-pregnadiene-3 ,20-dione,

906-bI'OIT10-1 l fl-chloro- 17 OL,2 1-dihydroxy-6-fluoro-1 6,6-

rnethyl-4,6-pregnadiene-3,ZO-dione,

90r-bromo-1 lfl-chloro-1700,21-dihydroxy-6-fluoro-16- methylene-4,6-pregnadiene-3,20-dione,

9a-bromo-11fi-chloro-l70t,21-dihydroxy-6-methyl-4,6-

pregnadiene-3,20-dione,

90c-bromo-l lfi-chloro170t,21-dihydroxy-6,16ot-dimethy1- 4,6-pregnadiene-3 ,20-dione,

90c-bromo-1lfl-chloro-1704,21-dihydroxy-6-methyl-16- methylene-4,6-pregnadiene-3,20-dione and the like.

The above named starting materials for our invention can be prepared by the introduction of the various substituents, namely the t-methyl-, 16B-methyl-, 16-metl1- ylene-, 600-rnethyl-, 600-fluoro-, 900-fiuoro or the 90t-chloro groups into a ,21-dihydroxy-4-pregnene-3,ZO-dione according to known procedures capable of general application. More than one substituent may be introduced into the unsubstituted steroid in any order, although it is generally preferred to introduce a Qua-halogen substituent last,

Anllfl, 170:,21-trihydroxy-4-pregnene-3,20- dione compound may be converted into the correspondingly substituted 90t,11,8-dichloro-. or the 90t-bromo-11fi-chlorol70,2l-dihydroxy-4-pregnene-3,ZO-dione compound by first dehydrating the llfi,170t,21-trihydroxy-4-pregnene- 3,20-dione at the 9(11)-position to form the corresponding 9(11)-pregnene, then acetylating at the 2l-position, and finally halogenating at the 901,1 iii-positions, for example, following the detailed procedures given in column 29..

All of the above 1700,2l-dihydroxy-4-pregnene-3,20 dione compounds may be converted into the correspond-- ing 170t-21-dihydroxy4,6-pregnadiene-3,20-dione com-- pounds by chloranil dehydrogenation, preferably of the 21-ester, in order to prevent extensive degradation of the dihydroxyacetone side chain, for example, following the detailed procedure on page 73, which is of general application. Alternately, chloranil dehydrogenation takes place as an intermediate step in the preparation of the desired starting material.

It has been found that the starting materials defined above will react with aqueous formaldehyde solutions in the presence of strong acid to form compounds having the formula:

wherein R is fl-hydroxy or ,B-halogen but B-halogen is O Ca I I /GH2 "-0 wherein R R and X have the significance above defined, 18 prepared by oxidation of the corresponding 1158- hydroxy 17a,20,20,21 bis(methylenedioxy)-4,6-pregnadiene-3-one, for example, with chromium trioxide in a non-aqueous base such as pyridine. If desired, however, the 17oc,20,20,21 bis(methylenedioxy)-4,6-pregnadiene 3,1l-dione may be prepared directly by the reaction of the 17a,21-dihydroxy-4,6-pregnadiene-3,11,20-trione with formaldehyde solution in the presence of an acid as described in the preceding step.

Upon treatment of an 11,8-hydroxy-, 11B-halogen-, or 1l-keto-17a,20,20,21 bis(methylenedioxy) 4,6 pregnadiene-3-one compound with an alkyl formate and sodium hydride in an inert atmosphere there is formed the corresponding -17a,20,20,21 bis(methylenedioxy)-2-hydroxymethylene-4,6-pregnadiene-3-one which has the followwherein R is Si-halogen, ,B-hydroxy and/or fi-formyloxy-, or keto-, but B-halogen is present at R only when X is halogen, and R R and X have the significance above defined. the steroid is dissolved in a solvent such as benzene and the resulting solution is cooled to room temperature and treated with ethyl formate. The air in the systern is replaced with nitrogen, sodium hydride is added and the mixture is stirred at room temperature for several hours.

The l7a,20,20,21-bis(rnethylenedioxy)-2-hydroxymethylene-4,6-pregnadiene-3-one compound reacts with hydrazine in an inert atmosphere to form the corresponding 17oc,20,20,21 bis(methylenedioxy)-4,6-pregnadieno- [3,2-c]pyrazole.

Upon treatment of a 17a,20,20,2l-bis(methylenedioxy) Z-hydroxymethylene 4,6 pregnadiene-3-one compound with a lower alkanol in the presence of an acidic reagent such as p-toluenesulfonic acid the corresponding 17a,20,20,2l-bis(methylenedioxy)-2-alkoxymethylene-4,6- pregnadiene-3-one is formed. When the latter compound is reacted with a mono-substituted hydrazine, the corresponding N substituted-4,6-pregnadieno-[3,2-c1pyrazole compounds are formed. The N-substituted-4,6-p-regnadieno-[3,2-c]pyrazoles having structure A are designated as the 1'-substituted-4,6-pregnadieno [3,2-c1pyrazoles, and the N-substituted-pyrazole compounds have oles, and the Nsubstituted-prazole compounds having structure B are designated as the 2-substituted-4,6-

In a preferred embodiment of our invention,

wherein R R R and X have the significance above defined, and wherein R is an alkyl, cycloalkyl, aralkyl or an a-ryl group. The products formed may be separated by chromatography.

Upon treatment of a 17u,20,20,21 bis(methylenedioxy) 2 hydroxymethylene 4,6 pregnadiene 3 one compound directly with a monosubstituted arylhydrazine, without the intermediate formation of the 2 alkoxymethylene-derivative, one isomer is generally formed in preponderant amounts, whereas when reacting the 170:, 20,20,21 bis(methylenedioxy) 2 alkoxymethylene- 4,6 pregnadiene 3 one compound with a monosubstituted arylhydrazine, signaficant amounts of both isomers are obtained. When these reactions take place with monosubstituted alkylhydrazines, mixtures may be obtained when starting with the 2 hydroxymethylenesteroid as well as with the 2 alkoxymethylene steroid. A mixture of isomers may also result from the reaction of a monosubstituted hydrazine with a 2-hydroxymethylene-compound which possibly contains variable amounts of the 2-alkoxymethylene-derivative due to the operating procedures employed, for example, due to recrystallization in the presence of a trace of alcohol a solution of the 2-hydroxymethylene-compound from which acid has not been completely removed.

Among the monosubstituted hyd-razines which may be used for the process of our invention are: alkylhydrazines, such as methylhydrazine, ethylhydrazine, propylhydrazines, butylhydrazines, [i hydroxy ethylhydrazine, cycloalkylhydrazines; arylhydrazines including phenylhydrazine and the substituted phenylhydrazines, such as 0-, m-, and p-halophenylhydrazines, o-, m-, and p-tolyhydrazines, o-, m-, and p-alkoxyphenylhydrazines, o-, m-, and p-nitrophenylhydrazines, l-hydrazinonaphthalene, 2- hydrazinopyrid-ine, 3-hydrazinopyridine, 4-hydrazinopyridine, 4-hydrazinopyridine oxide, and Z-hydrazinopyrimidine; aralkylhydrazines, such as benzylhydrazine and phenylethylenehydrazine.

There are thus produced the corresponding N-substituted 4,6 pregnadieno [3,2-c1pyrazoles including: N-alkyl such as N-methyl-, N-ethyl-, N-butyl-, N-propyl-, N-(B-hy.droxyethyl)-; N-cycloalkyl-; N-arylwhich may be derived from any aromatic nucleus, 1 including N-phenyland the N-substituted-phenyl derivatives such as 0-, m-, and p-halophenyl; o-, m-, and p-tolyl-; o-, m-, and p-alkoxyphenyl-, o-, m-, and p-nitrophenyl-; N-(1- p y1)- "-pY y "-Py y "-py- 1'idyl)-, N-(4-pyridyloxide)-, N-(2"-pyrimidyl)-; N- N-aralkyl-, such as N-benzyland N-phenylethenyl-4,6- pregnadieno-[3,2-c1pyrazoles.

The N alkyl 4,6 pregnadieno [3,2-c]pyrazoles may also be prepared by direct alkylation of the N-unsubstituted 4,6 pregnadieno [3,2-c]pyrazoles.

A 17a,20,20,21 bis(methylenedioxy) 11 3 hydroxy 4,6 pregnadieno [3,2-clpyrazole which has a halo substituent is preferably prepared by the following alternate route. Using the procedures described above, the 90; halo 1l 8,l7a,21 trihydroxy 4,6 -pre'gnadiene 3,20 dione is converted into the corresponding 4 17a,20,20,21 bis(methylenedioxy) 9m halo 11B hydroxy 4,6 pregnadiene 3 one. The latter compound is then oxidized to the 1700,20,20,21 bis(methylenedioxy) 9a halo 4,6 pregnadiene 3,11 dione, which is reacted with ethyl formate and sodium hydride to form the 2-hydroxymethylene-derivative. The latter compound is reacted with hydrazine, or a monosubstituted hydrazine, to give the corresponding 17a,20, 20,21 bis(methylenedioxy) 9m halo 11 oxo 4,6- pregnadieno [3,2-c]pyrazle compound, or the N-substituted derivative thereof. The latter compound is then reduced to the corresponding 17a,20,20,21 bis(methylenedioxy) 9m halo 11B hydroxy 4,6 pregnadieno- [3,2-c]pyrazole compound, for example, by adding a saturated solution of sodium borohydride to a solution of the steroid in a mixture of triethylamine and isopropyl alcohol to which we prefer to add a little water, and allowing the mixture to stand overnight.

The N unsubstituted 17a,20,20,21 bis(methylenedioxy) 4,6 pregnadieno [3,2-c1pyrazole compounds are converted into N-acyl-derivatives having the following structures:

wherein'R is fi-halogen, fl-hy'droxy or keto, but [Si-halogen is present at R only when X is halogen; R R and X have the meaning described above; and wherein R is an acyl group, by treating with an acylating agent, e.g.

'a lower hydrocarbon carboxylic acid acylating agent .ample, a 60% aqueous solution of formic acid, the 17a,20,20,21 bis(methylenedioxy) protecting group is removed and there is obtained the corresponding 1706,21-

dihydroxy 20 oxo 4,6 pregnadieno [3,2-c1pyraace /3194 0 zoles which are represented by structures A and B:

553E W IT wherein R is fi-halogen, fi-hydroxy or keto, but B-halogen is present at R only when X is halogen; R R and X have the meaning described above; and wherein R is acyl, alkyl, cycloalkyl, aryl or aralkyl and R is hydrogen, an acyl group corresponding to the organic acid used in this reaction, or a mixture of the two.

Any acyl groups present at R; and/ or at R may be removed by treating the steroid with sodium methoxide in methanol at room temperature to form the corresponding :,21 dihydroxy 20 oxo 4,6 pregnadfeno- [3 2-c]pyrazole. Acyl groups present at the R position may be selectively removed by treatment with aqueous acetic acid.

The compounds of our invention include, among others, the following:

11B,17u,21-trihydroxy-20-oxo-4,6-pregnadieno-[3,2-c]- pyrazole,

1 1,8, 17u,21-trihydroxy-16a-methyl-ZO-oxo-4,6-pregnadieno- [3,2-c1pyrazole,

1lfl,17a,21-trihydroxy-16fi-methyl-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole,

1 1B,17a,21-trihydroxy-16-methylene-20-oxo-4,6-pregnadieno- [3 ,2-c] pyrazole,

115,170:,21-trihydroxy-6-methyl-20-oxo-4,6-pregnadieno- [3,2-c] pyrazole,

1 1B,17a,21-trihy.droxy-6,16a-dimethyl-Z0-oxo-4,6-pregnadieno- [3 ,2-c] pyrazole,

11/3,17ot,21-trihydroxy-6,16/3-dimethyl-ZO-oxo4,6-pregnadieno- [3 ,2-c] pyrazole,

11,8,l7a,21-trihydroxy-6-methyl-16-methylene-20-oxo- 4,6-pregnadieno- 3,2-c] pyrazole,

6-fluoro-1 1/3,17a,21-trihydroxy-20-oxo-4,6-pregnadieno- [3,2-c] pyrazole,

6-fluoro-1 1B,17a,21-trihydroxy-16a-methyl-20-oXo-4,6-

pregnadieno- 3,2-c] pyrazole,

6-fluoro-1 1,8, 17a,21-trihydroxy-16fi-methyl-20-oxo-4,6-

pregnadieno- [3 ,2-c] pyrazole,

6-fiuoro-l 1[3,17a,2l-trihydroxy-l6-methylene-20-oxo-4,6-

pregnadieno-[3,2-c1pyrazole,

9rx-iluoro-l 1B,17a,21-trihydroxy-16a-methyl-20-oxo-4,6-

pregnadieno- [3,2-c1pyrazole,

9a-fluoro-1 1B-17a,21-trihydroxy-1Gmethylene-ZO-oxo- 4,6-pregnadieno- [3,2-c]pyrazo1e,

9ot-ch1or0-11B,17ot,21-trihydroxy-ZO-oxo-4,6-pregnadieno- [3 ,2c] pyrazole,

9a-chlO1O-1 1,8,17a,21-tribydroxy-l6a-methyl-20-oXo-4,6-

pregnadieno- 3 ,2-c] pyrazole,

9a-chloro-1 15,l7a,21-trihydroxy-16,6-n1ethy1-20-0xo-4,6-

pregnadieno- 3 ,2-c] pyrazole,

9a-chloro-115,17a,21-trihydroxy-16-methy1ene-20-oxo- 4,6-pregnadieno- [3 ,2-c] pyrazole,

9u-fluoro-1 15,17u,21-trihydroxy-6-methyl-20-oxo-4,6-

pregnadieno- [3,2-c1pyrazole,

9a-fiuoro-1 1/8,17u,21-trihydroxy-6,16a-dimethyl-20-oxo- 4,6-pregnadieno- 3,2-c] pyrazole,

9a-fluoro-11B,17a,21-trihydroxy6,16,8-dirnethyl-20-oxo- 4,6-pregnadieno-[3,2-c1pyrazole,

9ot-fluoro-1 15,17a,21-trihydroxy-6-methyl-16-methylene- -oxo-4,6-pregnadieno-[3,2-c1pyrazole,

9a-chloro-1 1,8,17a,21-trihydroxy-6-methyl-20-oxo4,6-

pregnadieno- [3,2-c] pyrazole,

9u-chloro-l1B,17a,21-trihydroxy-6,16u-dimethyl-20-oxo- 4,6-pregnadieno-[3,2-c1pyrazole,

9a-chloro-11,9,17a,21-trihydroXy-6,16fl-dirnethy1-20-oxo- 4,6-pregnadieno- 3 ,2-c] pyrazole,

90t-ChlOlO-1 1B, 170:,21-trihydroXy-6-methyl-1fi-methylene- 20-oxo-4,6-pregnadieno- [3 ,Z-c] pyrazole,

9a-chloro-6-fluoro-l1,9,l7a,21-trihydroXy-20-oxo-4,6-

pregnadieno- 3,2-c] pyrazole,

9a-chloro-6-fiuoro-l 113, 17,2 1-trihydroxy-16ot-methy1-20- oXo-4,6pregnadieno- [3 ,2-c] pyrazole,

9a-chloro-6-fluoro-1 1,6,17,2l-trihydroxy-16p-methyl-20- oxo-4,6-pregnadieno- 3,2-c] pyrazole,

9OL-ChlOI'O-6-fluO1'O-1 1 3, 17 11,2 1 -trihydroxy-16-methylene- 20-oxo-4,6-pregnadieno- [3,2-c1pyrazole,

6,9u-difiuoro-l1B,17a,21-trihydroxy-20-oxo-4,6-pregnadieno- 3,2-c] pyrazole,

6,9u-difluoro-1 1B, 17,2 l-trihydroxy-16p-methyl-20-oxo- 4,6-pregnadieno- [3 ,2-c] pyrazole,

6,9a-difluoro-1 1p,17ot,21-trihydroxy-16-methylene-20- oxo-4,6-pregnadieno- 3,2-c1pyrazole,

and the ll-oxo-analogues of all of the above compounds, the

90:,1 lfl-dichloro-17a,21-dihydroxy-20-oxo-4,6-pregnadieno- 3 ,2-c1pyrazole, 911,1lfl-dichloro-17a,21-dihydroxy-16a-methy1-20-oxo- 4,6-pregnadieno 3 ,2-c] pyrazole, 9a,11fl-dichloro-17u,21-dihydroxy-16(3-methyl-20-oxo- 4,6-p1'egnadieno- 3,2-c] pyrazole, 90:,1lfl-dichloro-l7a,21-dihydroxy-16-methylene-20-oxo- 4,6-pregnadieno- 3 ,2-c] pyrazole. 906,11B-dlChlOI'O-6-flllOIO-1706,21-d'ihydrOXy-20-OXO-4,6-

pregnadieno- [3 ,2-c] pyrazole, 9u,1lfi-dichloro-6-fiuoro-17a,21-dihydroxy-16ot-methyl- 20-oXo-4,6-pregnadieno- [3 ,2-c1pyrazole, 9a,1 1,8-dichloro-6-fluoro-l7a,21-dihydroxy-16g8-methyl- 20-oXo-4,6-pregnadieno- 3,2-c] pyrazole, 90:,1lfl-dichloro-6-fluoro-17a,2l-dihydroxy-l6-methy1ene- 20-oxo-4,6-pregnadieno- [3 ,2-c]pyrazo1e, 9a,1lfi-dichloro-17a,21-dihydr0xy-6-methyl-20-oxo-4,6-

pregnadieno- [3,2-c1pyrazole, 9a,1lfl-dichloro-17a,21-dihydroxy-6,16u-dimethyl-20- oxo-4,6-pregnadieno-[3,2-c1pyrazole, 9a,11,8-dichloro-17a,21-dihydroxy-6,1613-dimethyl-20- oxo-4,6-pregnadieno-[3,2-c1pyrazole, 9a,1lfi-dichloro-17a,21-dihydroxy-6-rnethyl-16-methylene-ZO-oXo-4,6-pregnadieno- 3,2-c] pyrazole, 9u-bromo-11B-chloro-17ot,21-dihydroxy-20-oxo-4,6-

pregnadieno- 3 ,2-c] pyrazole, 9ot-bromo-11B-ch1oro-17ot,21 dihydroxy-16ot-methy1-20- oxo-4,6-pregnadieno-[3,2-c1pyrazole, 9a-bromo-1 1B-chloro-l'7a,2 l-dihydroxy- 16 3-methyl-20- oxo-4,6-pregnadieno- 3,2-c] pyrazole,

9a-bromo-l 1 3-chloro-17a,21-dihydroxy-16-methylene- 20-oXo-4,6-pregnadieno- 3,2-c] pyrazole, I

9a-bromo-1 1B-chloro-6-fluoro-17a,2l-dihydroxy-ZO-oxo- 4,6-pregnadieno- [3,2-c1pyrazole,

9a-bromo-1 1/3-chloro-6-f1uoro-l7a,2 l-dihydroxy-16B- methyl-20-oxo-4,6-pregnadieno-[3,2-c1pyrazole,

9a-bromo-l lfi-chloro-l7a,21-dihydroxy-6-methyl-20-oxo- 4,6-pregnadieno- 3,2-c] pyrazole,

9a-bromo-1 1 fl-chloro- 17 11,2 l-dihydroxy-G, 16ot-dimethyl- 20-oxo-4,6-pregnadieno- 3,2-c] Pyrazole,

9a-bromo-l 1fl-ch1oro-17a,2 1-dihydroxy-6, l 6 3-dimethyl- 20-oxo-4,6-pregnadieno- [3 ,2-c] pyrazole and 9ot-bromo-1lfi-chloro-17a,21-dihydroxy-6-methy1-16- methy1ene-20-oxo-4,6-pregnadieno- [3,2-c] pyrazole as well as the 1'-and 2-alkyl-, the 1'-and 2'-cyc1oalkyl the 1' and 2'-aryl-, and the 1' and 2'-aralkyl-derivatives of all of the above named compounds.

The N-acyl-derivatives of the above described 17,21- dihydroxy-20-oxo-4,6-pregnadieno-[3,2-c] pyrazoles are prefer-ably obtained by treating the corresponding N-acyl- 17ot,20,20,21 -bis(methyler1edioxy)-4,6-pregnadieno-[3,2- c]-pyrazole compound with a dilute organic acid to remove the c,20,20,21 bis(methylenedioxy) protecting group.

The 21-acyl derivatives of the above described 170t,2l dihydroxy 20 oxo 4,6-pregnadieno-[3,2-c1pyrazoles in which R is H may be prepared by heating an N-acyl-17u, 21-dihydroxy-20-oxo-4,6-pregnadieno- [3,2-c1pyrazole 21- acylate with aqueous acetic acid, whereupon the N-acylgroup is selectively removed.

The N-acyl-Zl-acylat'e derivatives of the above de scribed 17,21-dihydroxy-ZO-oxo-4,6pregnadieno-[3,2-c] pyrazoles in which both acyl groups are the same may be prepared (1) by reacting a 170:,21-dihydroxy-20-oxo-4,6- pregnadieno-[3,2-c1pyrazole with two equivalents of an acylating agent or (2) by reaction of an N acyl-17a,21- dihydroxy 20 oxo-4,6-pregnadieno-[3,2-c1pyrazole with one equivalent'of an acylating agent in which the acyl group of the acylating agent is the same as the acyl group already present at the N-position of the pyrazole.

The N-acyl-Zl-acylate derivatives of the above described 17a,21-dihydroXy-20-oXo-4,6-pregnadieno-[3,2-c] pyrazoles in which the acyl groups are different are prepared by reaction of an N-acyl-17u,21-dihydroxy-20-oxo- 4,6-pregnadieno-[3,2-c]py1razole with an acylating agent in which the acyl group of the acylating agent is different from the acyl group already present at the N-position of the pyrazole.

Acylating agents which can be used for this purpose include a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride, tertiary butyl acetyl chloride; a lower alkanoic anhydride or lower alk-anoyl halide such as acetic anhydride, propionic anhydride; or a polybasic anhydride such as fifi-dirnethyl-glutaric anhydride, succinic anhydride and the like, in the presence of an organic base such as pyridine.

The 170:,21 dihydroxy-ZO-oxo-4,6-pregnadieno-[3,2-c] pyrazole is reacted with methane sulfonyl chloride in a non-aqueous base to form the 21-rncsylate. A steroid in which R is hydrogen is preferably converted to the N- acyl derivative before undergoing this reaction.

The 170:,21 dihydroxy-ZO-oxo-4,6 pregnadieno-[3,2-c] pyrazole 2l-mesylate is heated with an alkali iodide to form the 21-iodo-compound. In a preferred method for carrying out this reaction, sodium iodide is added to the steroid dissolved in acetone and the resulting mixture is heated at reflux temperature for approximately one hour.

The 17a-hydroxy-21-iodo-20-oxo-4,6-pregnadieno-[3,2- c]pyrazo1e is heated with an alkali bisulfite in a solvent to form the corresponding 21-desoxy-eompound which have the structures A and B:

wherein R R R R and X have the significance above defined. A preferred method is to add sodium bisulfite to a suspension of the steroid in aqueous ethanol and then heat the mixture under reflux for a period of about an hour.

Thus the novel compounds of our invention which are formed from the above reactions include:

11,8,17u-dihydroXy--oxo-4,6-pregnadieno-[3,2-c]

pyrazole 1 15, 1 704,-dihYdI'0XY- 1 6a-methy1-20-oxo-4,6-pre gnadieno- [3 ,2-c] pyrazole 11,13,170 dihydroxy 16fl-methy1-20-oxo-4,6-pregnadieno- 1 15, 17a-dihydroxy16-1nethyiene-20-oxo-4,6-pregnadieno- [3 ,2-c]pyrazo1e 115,17a-dihydroxy-6-methy1-20-oxo-4,6-pregnadieno-[3,2-

c]py\razo1e 11 3,17a-dihydroXy-6,16a-dimethy1-2O-ox0-4, 6 pregnadieno- 3,2-c1pyrazo1e 1 1/3, 17a-dihydroxy-6, 16B-dimethy1-20-oxo-4,6-plregnadieno- [3 ,2-c]pyrazo1e 1 1/3,17a-dihydroxy-6-methy1-16-methylene-20-oxo-4,6-

pregnadieno- [3 ,2-c]pyrazo1e 6-fluoro-11p,17a-dihydroxy-20-oX0-4,6-pregnadieno- [3 ,2-c] pyrazole 6-fiuoro-1 1,8,17u-dihydroxy-16a-methy1-20-oXo-4,6-

pregnadieno-[3,2-c1pyrazo1e 6-fluoro-1 1,8,17a-dihydroxy-16/3-methyl-20-oxo-4,6-

pregnadieno- [3 ,2-c1pyrazo1e 6-fluoro-11B,17a-dihydroxy-16-methy1ene-20-oXo-4,6-

pregnadieno- [3 ,2-c]pyrazo1e 9ot-fiuor0-1 15,17ot-dihydroxy-20-oxo-4,6-pregnadieno- 9u-fluor0-1 1 6,17a-dihydroxy-16a-methy1-20-oxo-4,6-

pregnadieno- 3 ,2-c1pyrazo1e pregnadieno- [3,2-c]pyrazo1e 9a-chloro- 11B,17a-dihydroxy-16fl-methy1-20-oxo-4,6-

pregnadieno- [3,2-c1pyrazo1e pregnradieno- 3,2-C1PYnazol 13 9ot-brOrn0-l 1 p-chloro-17a-hydroxy-6-rnethyl-20-oxo- 4,6-pregnadieno-[3,2-c1pyrazole 9a-bromo-11,8-chloro-17m-hydroxy-6,16a-dimethyl-20- oxo-4,6-pregnadieno-[3,2-c1pyrazole 9oc-br-omo-lLIB-chloro-17u-hydroxy-6,16fl-dimethyl-20- oxo-4,6-pregnadieno-[3,2-c1pyrazole 9oc-b1'0m0-l 1 fi-chloro- 1 7a-hydroxy-6-methyl-1 6-methy1- ene-Z-oxo-4,6-pregnadieno-[3,2-c1pyrazole as well as the 1- and 2'-alkyl-, the 1'- and 2'-cycloalkyl-, the 1'- and 2'-aryl-, the 1'- and 2'-aralkyland the N- acyl-derivatives of all of the above named compounds. The ZI-dihydrogen phosphate esters are prepared by the reaction of the corresponding 21-iodo compound with a mixture of silver phosphate and phosphoric acid. Both the monoand dialkali metal salts may be obtained by neutralization of the dihydrogen phosphate ester with an alkali methoxide. Treatment with additional amounts of alkali methoxide will convert an N-acyl-steroid (R acyl) into the free amine (R H) dialkali metal salt from which the dihydrogen phosphate can be obtained by con tacting with an ion exchange resin.

The A, B, C and pyrazole rings are not shown in the above equation, as the substituent groups on these rings do not affect the course of reaction and in general are unchanged during reaction. R has the meaning above defined and X is halogen.

The 21 fluoro 17a hydroxy-20-oxo-4,6-pregnadieno- [3,2-c1pyrazoles are prepared from the corresponding 17 a,2 1-dihydroxy-20-oxo-4,6-pregnadieno- 3,2-c] pyrazole 2l-mesylate by heating with an alkali fluoride in a solvent to form a mixture of a l7a,2l-epoxy-compound and the corresponding 21-fiuoro compound. These compounds are separated by partition chromatography, or by chromatography on a weak adsorbent such as silica gel. There is thus obtained the 2l-fluoro-derivatives of all of the compounds named on pages 3-6. The 21-fluoro'derivatives are represented by structures A and B:

wherein R R R R and X have the significance above described. All of the 4,6-pregnadieno-[3,2-c] pyrazoles described in the foregoing structures form salts such as the hydrochloride, sulfate, chlorate, perchlorate, picrate and trichloroacetate, on treatment with the corresponding acid. Formation of crystalline salts, especially the hydrochloride salts, provides a means of isolating the 4,6-pregnadieno-[3,2-c]pyrazoles.

A further embodiment of our invention comprises novel pharmaceutical compositions containing the novel 4,6- pregnadieno-[3,2-c1pyrazoles exemplified in the foregoing structures.

The following examples illustrate methods of carrying out the present invention but it is to be understood that these examples are given for purposes of illustration and not of limitation. Details of the above described reactions are to be found in the examples.

Example 1 To a suspension of 25.0 g. of 11p,17u,21-trihydroxy-4,6- pregnadiene-3,20-dione in 1.5.1. of alcohol-free chlorofor-m cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two U.V. absorbing spots near the solvent front (methanol-formamide 221 vs. benzene-n-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,20,2l-bis(methylenedioxy)-ll/3-hydroxy-4, 6-pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification.

A solution of 400 mg. of 17a,20,21-bis(methylenedioxy)-l1B-hydroxy-4,6-pregnadiene 3 one in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then with water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 17a,20,20,2l-bis(rnethylenedioxy)-4,6- pregn adiene-3 ,1 l-dione.

The 17a,20,20,21-bis(methylenedioxy) 4,6 pregnadiene-3,l1-dione (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,2l-bis(methylenedioxy) -2-hydroxymethy1- ene-4,6-pregnadiene-3 ,1 l-dione.

The 17a,20,20,21-bis(methylenedioxy) 2 hydroxymethylene-4,6-pregnadiene-3,1l-dione (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17a,20,20,21-bis(methylenedioxy)- 11-oxo-4,6-pregnadieno-[3,2-c] pyrazole.

To a solution of 100 mg. of l7u,20,20,2l-bis(methylenedioxy)-ll-oxo-4,6-pregnadieno-[3,2-c] pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3 saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-17a,20,20,21-bis(methylenedioxy)-11-oxo-4,6-pregnadieno-[3,2-c] pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N- acyl derivative.

The N-acetyl-l7a,20,20,21-bis(methylenedioxy) 11- t oxo-4,6-pregnadieno-[3,2-c pyrazole] (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about minutes. reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high 'vacuum to give an amorphous solid which is a mixture of N-acetyl-l7ot,2l-dihydroxy-l l,20-dioxo-4,6 pregnadieno- [3,2-c]pyrazole and N-acetyl-2l-formlyoxy-Net-hydroxyll,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 m. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17a,21-dihydroxy- 11,20-dioxo-4,6-pregnadieno-[3,2-c1pyrazole.

To a solution of 100 mg. of N-acetyl-17a,21-dihydroxyll,20-dioxo-4,G-pregnadieno-[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-l7a,2l-dihydroxy-l1,20-dioxo-4,6-pregnadieno-[3,2-c1pyrazole 21-acetate which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of aceiit: anhydride, there is obtained the corresponding The excess 16 N acetyl-l7u,2l-dihydroxy-l l,20-dioxo-4,6-pregnadieno [3,2-c]pyrazole 2l-acyla te.

In accordance with the above procedure, but starting with the l7a,2l-dihydroxy-l1,20-dioxo-4,6-pregnadieno- [3,2-c]pyrazole, and using two milliequivalents of another acylating agent there is obtained the corresponding N- acyl-2l-acylate thereof.

A solution of 5.73 g. of N-acetyl-17ot,21-dihydroxy- 11,20-dioxo-4,6-pregnadieno- 3,2-c] pyrazole 2 l-acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted wth 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extracts are washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 17u,2l-dihydroxy-11,20-dioxo-4,6-pregnadieno- [3,2-c1pyrazole 2l-acetate.

To a solution of mg. of N-acetyl-17a, 21-dihydroxy- 11,20-dioxo-4,6-pregnadieno-[3,2-c]py-raz0le in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-l7a,21-dihydroxy-ll,20dioxo-4,6-pregnadieno- 3,2-c] pyrazole 21rmesylate.

To a 180 mg. of N-a-cetyl-17a,21-dihydroxy-11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole 2l-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N acetyl-17u-hydroxy-21-iodo-1l,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole.

The N acetyl l7a-hydroxy-2l-iodo-l l,20-dioxo-4,6- pregnadieno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-l7a-hydroxy-l1,20-dioxo 4,6-pregnadieno-[3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with Water, filtered and dried to constant weight to give 17a-hydroxy-ll,20- dioxo-4,6-pregnadieno-[3,2-c]pyrazole.

To a solution of 62 mg. of N-acetyl-l7oz,2l-dihydroxy- 1 1,20-dioxo-4,6-pregnadieno- [3,2-c1pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. (for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-l7a,21-epoxy-11,20-dioxo-4,6- pregnadieno-[3,2-c]pyrazole and N-acetyl-Zl-fiuoro-lhhydroxy 11,20 dioxo 4,6-pregnadieno-[3,2-c]py'razole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed 17 with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 21-fluoro-17ahydroxy-11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole.

In accordance with the above procedures, but starting with the 11B, 170:, 2l-trihydroxy-l6a-methyl-4,6-pregnadiene-3,20-dione or 11,8, 170:, 21-trihydroxy-l6B-methyl-4,6-pregnadiene-3,20-dione in place of the 115,17u, 21-trihydroxy-4,6-pregnadiene-3,20-dione, there are obtained as products the corresponding 1700,21-dihYCl1'0XY 16oz methyl 11,20 dioxo 4,6 pregnadieno [3, 2-c]pyrazole or 17a,21-dihydroxy-16/3-methyl-11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole, and the N-acyl-, the 21-acylate, and the N-acyl-Zl-acylate derivatives thereof; the 170s hydroxy 16a methyl 11,20 dioxo 4, 6- pregnadieno [3,2-c1pyrazole or 17a hydroxy 16 6- methyl 11,20 dioxo 4,6 pregnadieno [3,2-c]pyrazole and the N-acyl-derivatives thereof; and the 21- fluoro 17a hydroxy 16a methyl 11,20 dioxo- 4,6 pregnadieno [3,2-c]pyrazole or 21 fluoro 170chydroxy 16/3 methyl 11,20 dioxo 4,6 pregnadieno-[3,2-c]pyrazole and the N-acyl derivatives thereof.

In accordance with the above procedures, but starting with the 11 B,l7u,21-trihydroxy-16-methylene-4,6-pregnadiene-3,20-dione in place of the 11fi,17a,2l-trihydroxy 4,6-pregnadiene-3,20-dione, there are obtained as products the corresponding 17a,2l-dihydroxy-l-fi-methylene- 11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole and the N- acyl, the 21-acylate, and the N-acyl-21-acylate derivatives thereof; the 17a-hydroxy-16-methylene-11,20-dioxo- 4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl derivatives thereof; and the 21-fluoro-17u-hydroxy-16-methylene 11,20 dioxo 4,6 pregnadieno [3,2-c1pyrazole and N-acyl derivatives thereof.

Example 2 To a suspension of 25.0 g. of 6-fluoro-l1B,17a-2l-trihydroxy-4,6-pregnadiene-3,20-dione in 1.5 liters of alcohol-free chloroform cooled to about C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesiumsulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but show two U.V. absorbing spots near the solvent front (methanolformamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 6-fiuoro-17a,20,20,2l-bis- (methylenedioxy) 115 hydroxy 4,6 pregnadiene- 3-one, which is used in the subsequent step of the synthesis without further purification.

The 17oc,20,20,21 bis(methylenedioxy) 6 fluoro- 11 B-hydroxy-4,6-pregnadiene-3-one (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with Water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17u,20,20,2l-bis(methylenedioxy) 6 fluoro 115 hydroxy 2 hydroxy methylene-4,6-pregnadiene-3-one.

The 17a,20,20,21 bis(rnethylenedioxy) 6 fluoro- 11B hydroxy 2 hydroxymethylene 4,6 pregnadiene- 3-one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at C. for 1 hour in high vacuum to give l7oc,20,20,21 bis(methylenedioxy) 6 fluoro 11B- hydroxy-4,6-pregnadieno-[3,2-c]pyrazole.

To a solution of mg. of l7u,20,20,21--bis(methylenedioxy) =6 fluoro 11/3 hydroxy 4,6 pregnadieno- [3,2-clpyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is al'owed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-17a,20,20,21-bis(methylenedioxy)-6- fluoro 116 hydroxy 4,6 pregnadieno [3,2-c]pyraz= ole which is isolated by the addition of water and filtra tion.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N acetyl 17a,20,20,21 bis(methylenedioxy)-6- fluoro-ll,8hydroxy 4,6 pregnadieno-[3,2-c1pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60:

C. in high vacuum to give a solid which is a mixture of N acetyl 6 fluoro 11/8,17a,2l-trihydroxy-ZO-oxo- 4,6-pregnadieno-[3,2-c] pyrazole and N-acetyl-6-fluoro-2lformyloxyl 1113,17a-dihydroxy-20-oxo-4,6-pregnadieno- [3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 6-fluoro- 11B,17cc,21-trihydroxy 20 oxo 4,6 pregnadieno- [3,2-c1pyrazo1e.

To a solution of 100 mg. of N-acetyl-6-fiuoro-l118,17a, 21 trihydroxy 20 oxo 4,6-pregnadieno-[3,2-c]

pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3),

I saturated aqueous sodium bicarbonate (until the pH of the The alkoxide is neutralized with semen 19 neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afiord the N-acetyl-6-fiuoro- 11fl,'17u,21 trihydroxy-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole 21-acetate which is isolated by addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in plate of the acetic anhydr'ide, there is obtained the corresponding N-acetyl-6-fluoro-1l,B,17a,21-trihydroxy 20 oxo 4,6- pregnadieno- [3,2-c1pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 6 fluoro 11,8,17a,21-trihydroxy-20-oxo-4,6- pregnadieno-[3,2-c1pyrazole, and using two equivalents of another acylating agent there is obtained the corresponding N-acyl-Zl-acylate thereof.

A solution of 5.73 g. of N-acetyl-6-fluoro-11a,17a-21- trihydroxy 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole 21- acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of icewater and extracted with ethyl acetate. The ethyl acetate extract is washed with Water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 6 fiuoro 17a,2l-dihydroxy-11,20-dioxo-4,6- pregnadieno [3,2-c] pyrazole 21-acetate.

To a solution of 85 mg. of N-acetyl-6-fluoro-115,17u,21- trihydroxy-20-oxo-4,6-pregnadieno- 3 ,2-c] pyrazole in 0.5 ml. of pyridine, cooled to C. is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-6-fiuoro-l1B,17a,21-trihydroxy-20- oxo-4,6-pregnadieno- 3 ,2-c] pyrazole 21-mesylate.

To 180 mg. of N-acetyl-6-fluoro-11 3,17a,21-trihydroxy- 20-oxo-4,6-pregnadieno[3,2-c]pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-6-fluoro-1113,17a-dihydroxy-21-iodo-20-oxo- 4,6-pregnadieno-[3,2-c]pyrazole. v V

The N acetyl-6-fluoro-11fi,17a-dihydroxy-21-iodo-20 oxo-4,6-pregnadieno-[3,2-c]pyrazole is dissolved in a mixture of ml. of water and 5 ml. of ethanol. To the resulting suspension is aded 500 mg. of .sodium bisulfite and the mixture is heated under reflux for a period of about one hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-6- fluoro-11fl,17a-dihydroxy 20 oxo 4,6-pregnadieno- [3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid anl the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 6-fluoro- 115,17a-dihydroxy 20 oxo 4,6pregnadieno-[3,2-c] pyrazole.

To a solution of 62 mg. of N-acetyl-6-fluoro-11B,17a,21- trihydroxy 20-oxo-4,6-pregnadieno-[3,2c]pyrazole 21- mesylate in l-ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The re- 20 sulting product is a mixture of N-acetyl-17a,21-epoxy-6- fluoro-llB-hydroxy-ZO oxo 4,6 pregnadieno-[ 3,2-c] pyrazole and N acetyl-6,21-difluoro-11fi,17u-dihydroxy- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazo1e which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures, but starting with the corresponding N-acyl derivatives, there are obtained as products the N-acyl-6-fluoro-11B,17a-dihydroxy- 20-oxo 4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl- 6,21-difiuoro-11,8,17a-dihydroxy-20-oxo-4,6 pregnadieno- [3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give the 6,21- difluoro-l 113, 17a dihydroxy-20-0xo-4,6-pregnadieno [3,2-c] pyrazole.

In accordance with the above procedures, but starting with the 1 1B,17a,21-trihydroxy-6,16a-dimethyl-4,6-pregnadiene-3,20-dione in place of the 6-fiuoro-11fi,17a,21- trihydroxy-4,6-pregnadiene-3,20-dione there are obtained as products the corresponding 11fl,17ot,21-trihydroxy- 6,160: dimethyl 20-oxo-4,6-pregnadieno[3,2-c1pyrazole and the N-acyl-, the 2l-acylate, and the N-acyl-21-acylate derivatives thereof; the 11fl,17a-dihydroxy-16a-dimethyl- 20-oxo-4,6-pregnadieno[3,2-c]pyrazole and the N-acyl derivatives thereof; and the 21-fluoro-11fi,17a-dihydroxy- 6,1611 dimethyl 20-oxo-4,6-pregnadieno[3,2-c1pyrazole and the N-acyl derivative thereof.

Example 3 To a suspension of 25.0 g. of 11;8,17a,21-trihydroxy- 6-methyl-4,6-pregnadiene-3,20-dione in 1.5 l. of alcoholfree chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is backextracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chomatography but shows two U.V. absorbing spots near the solvent front (methanol-formamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,20,21-bis(methylenedioxy)-11,8- hydroxy-6-methyl-4,6-pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification.

A solution of 400 mg. of 17a,20,20,21-bis(methylenedioxy)--hydroxy-6-methyl-4,6-pregnadiene-3-one in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 17a,20,20,21-bis(methylenedioxy)-6- methyl-4,6-pregnadiene-3,1l-dione.

The 17m,20,20,21 bis(rnethylenedioxy)-6-methyl-4,6- pregnadiene-3,1l-dione (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,2l-bis(methylenedioxy)-2-hydroxymethylene-6-methyl-4,6-pregnadiene-3,1 l-dione.

The 17u,20,20,21 bis(methylenedioxy) 2 hydroxymethylene-6-methyl-4,6-pregnadiene-3,1l-dione (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17a,20,20,21-bis(methylenedioxy)- 6-methyl-11-oxo-4,6-pregnadieno-[3,2-c]pyrazole.

T o a solution of 100 mg. of 17a,20,20,21-bis-(methylenedioxy) 6-methyl-11-oxo-4,6-pregnadieno-[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulphuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8) and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C., in vacuo to afford the N-acetyl-17ot- 20,20,21 bis (methylenedioxy) -6-methyl-1 1-oxo-4,6-pregnadieno-[3,2-c]pyrazole, which is isolated by the addition of Water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N acetyl 17a,20,20,2l bis(methylenedioxy)-6- methyl 11 oxol4,6-pregnadieno-[3,2-c]pyrazole (720 mg.) is heated on a steam bath with 24 ml. of a 60% solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give an amorphous solid which is a mixture of N-acetyl 17or.,21 dihydroxy 6-methyl-11,20-dioxo-4,6- pregnadieno[3,2-c]pyrazole and N-acetyl-2l-formyloxy- 17cc hydroxy 6 methyl-11,20-dioxo-4,6-pregnadieno- [3,2-c1pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give l7a,2l-dihydroxy-6- methyl-1 1,20-dioxo-4,6-pregnadieno- [3 ,2-c] pyrazole.

To a solution of 100 mg. of N-acetyl-Hull-dihydroxy- 6 methyl-11,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-l7a,21-dihydroxy-6-methyl- 11,20 dioxo 4,6-pregnadieno-[3,2-c]pyrazole 21-acetate which is isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N acetyl 170:,21 dihydroxy-6-methyl-11,20-dioxo-4,6- pregnadieno-[3,2-c1pyrazole 21-acylate.

In accordance with the above procedures, but starting with the 17 11,2 l-dihydroxy-6-methy1-l l,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole, and using two milliequivalents of another acylating agent, there is obtained the corre sponding N-acyl-l7a,2l-dihydroxy-6-methyl-11, 20-dioxo-4,6-pregnadieno- 3,2-c] pyrazole 21-acylate.

A solution of 5.73 g. of the N-acetyl-flail-dihydroxy- -methyl-l l ,20-dioxo-4,6-pregnadieno [3 ,2-c]pyrazole 21- acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 17u,21-dihydroxy-6-methyl-11,20-dioxo- 4,6-pregnadieno-[3,2-c]pyrazole 21-acetate.

To a solution of mg. of N-acety1-17ot,21-dihydroxy- 6 methyl-1l,20-dioxo-4,6-pregnadieno-[3,2-c1pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-1715*,21-dihydroxy-6-methyl- 11,20-dioxo-4,6-pregnadien-o-[3 ,2-c]pyrazole 21-mesylate.

To 180 mg. of N-acetyl-:,21-dihydroxy-6-methyl- 1 1,20-dioxo-4,6-pregnadieno-[3,2-c]pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium idodide. The resulting mixture is heated at reflux temper-' ature for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N- acetyl 17oz hydroxy-21-iodo-6-methyl-1l,20-dioxo-4,6- pregnadieno-[3,2-c]pyrazole.

The N-acetyl 17cc hydroxy-21-iodo-6-methyl-11,20- dioxo-4,6-pregnadieno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N acetyl 17cc hydroxy 6 methyl 11,20 dioxo- 4,6-pregnadieno-[3,2-c1pyrazole.

A 500 mg. aliquot of the above'compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogenatmosphere for ten minutes. The alkoxide is neutralized with 23 acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17ahydroxy 6 methyl 11,20 dioxo- 4,6 pregnadieno- [3,2-c]pyrazole.

T o a solution of 62 mg. of N-acetyl-17a,21-dihydroxy- 6 methyl 11,20 dioxo 4,6 pregnadieno [3,2-c]- pyrazole 2l-mesylate in 1 ml. of freshly distilled anhy drous di-methylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evapo rated to dryness. The resulting product is a mixture of N acetyl 17a,2l epoxy 6 methyl 11,20 dioxo- 4,6 pregnadieno [3,2-c1pyrazole and N -acetyl 21- fluoro 17a hydroxy 6 methyl 11,20 dioxo 4,6- pregnadieno-[3,2-c]pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures, but starting with the 9e-fluoro ll/S,l7oc,2l trihydroxy-4,6-pregnadiene-3,20-dione in place of the 11,6,17a,21-trihydroxy- 4,6-pregnadiene-3,20-dione there are obtained as products the corresponding 9a-fiuoro-17a,21-dihydroxy-11,20- dioxo-4,6-pregnadieno-[3,2-c1pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-ZI-acyl-ate derivatives thereof in which the two acyl groups may be the same or different; the 9ot-flUOIO-17oc-hYd10XY-11,20-(li0X0-4,6- pregnadieno-[3,2-c]pyrazole and the N-acyl derivatives thereof; and the 9a,21-difiuoro-17a-hydroxy-11,20-dioxo- 4,6-pregnadiene-[3,2-c1pyrazole and the N-acyl derivatives thereof.

I n accordance with the above procedures, but starting with the 9e-fiuoro-6-methyl-11B,17a,21-trihydroxy-4,6- pregnadiene-3,20-dione in place of the 11B,l7a,2l-trihydroxy 6 methyl 4,6 pregnadiene 3,20 dione, there are obtained as products the corresponding 9afiuoro 170;,21 dihydroxy 6 methyl 11,20 dioxo- 4,6 pregnadieno [3,2 c]pyrazole and the N acyl-, the 21 acylate, and the N acyl 21 acylate derivatives thereof in which the two acyl groups may be the same or dilferent; the 9a-fiuoro-17a-hydroxy-6-methyl- 11,20-dioxo-4,6-pregnadieno-3,2-c pyrazole and the N- acyl derivatives thereof; and the 9a,21-dlfll.lOfO-170t-hydroxy 6 methyl 11,20 dioxo 4,6 pregnadieno- [3,2-c]pyrazole and the N-acyl derivatives thereof.

Example 4 To a suspension of 25.0 g. of 11/3,17a,21-trihydroxy- 16a-methyl-4,6-pregnadiene-3,20-dione in 1.5 liters of alcohol-free chloroform cooled to about C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bircarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography. A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,20,2lbis(methylenedioxy) 11p hydroxy 16cc methyl 4,6- pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification.

The 170: 20,20,21 bis(methylenedioxy) 1113 hydroxy 16a methyl 4,6 pregnadiene 3 one (1.350 g.) is dissolved in 25 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate.

The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give l7a,20,20,2l bis(methylenedioxy) 1113 hydroxy 2- hydroxymethylene 16oz methyl 4,6 pregnadiene 3- one.

The 17 a,20,20,2 l-bis methylenedioxy) -1 1 B-hydroxy-Z hydroxymethylenel 6u-methyl-4,6-pregnadiene-3-one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at C. for 1 hour in high vacuum to give 17u,20,20,21-bis(methylenedioxy)-l1,8-hydroxy-16a-methyl-4,6-pregnadieno [3,2-c] pyrazole.

To a solution of mg. of 17a,20,20,21-bis(methylenedioxy)-1 lfi-hydroxy-16u-methyl-4,6-pregnadieno [3, 2-c]pyra zole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl- -7oc,20,20,21 bis(methylenedioxy) llfl-hydroxy 16oz.- methyl-4,6-pregnadieno-[3,2-c1pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride there is obtained the corresponding N- acyl-steroid.

The N-acetyl-17a,20,20,21-bis(methylenedioxy)-1I a-hydroxy-16a-methyl-4,6-pregnadieno-[3,2-c]pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give an amorphous solid which is a mixture of N-acetyl-l1B,170:,21-trihydroxy-16u-methyl- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole and N-acetyl-Zlfo-rmyloxy 11B,-17a-dihydroxy 16u-methyl-20-oxo-4,6- pregnadieno-[3,2-c]pyrazole which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 m1. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with water, filtered and dried to constant weight to give 11B,17a,21-

25 trihydroxy 16wmethyI-ZO-oxo-4,6-pregnadieno [3,2-c] pyrazole.

To a solution of 100 mg. of N-acetyl-l1fi,17u,21-trihydroxy-l6a-methyl-20-oxo-4,6-pregnadieno-[3,2 clpyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The N-acetyl-llfi, 17a,21-trihydroxy 16ot-methyl-20-oxo-4,6 pregnadieno- [3,2-c1pyrazole 21acetate is then isolated by addition of Water and filtration.

In accordance with the above procedures. but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acetyl-1 1,8,17a,21-trihydroxy 16ot-methyl-20-oxo-4,6- pregnadieno-[3,2-c1pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 1lB,170t,21-tI'lhydlOXy-16CZ-II1Cthy1-20-OXO-4,6- pregnadieno-[3,2-c]pyrazole and using two milliequivalents of another acylating agent there is obtained the corresponding N-acyl-l1,8,17a,2l-trihydtroxy-16a-methyl-20 oxo-4,6-pregnadieno- [3,2-c] pyrazole 21-acylate.

A solution of 5.73 g. of N-acetyl-llfi,17u,21-trihydroxy-l6ot-methyl-20-oxo-4,6-pregnadieno-[3,2 c]pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords 11fi,17a,2l-trihydroxy-16ot-methyl-20-oxo- 4,6-pregnadieno-[3,2-c]pyrazole 21-acetate.

To a solution of 85 mg. of N-acetyl-11,3,17a,21-trihydroxy 16a-methyl-20-oxo-4,6-pregnadieno [3,2-c] pyrazole in 0.5 ml. of pyridine, cooled to C., is added 0015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtraction, washed with water, and dried to give N-acetyl-l1fi,17a,21-trihydroxy-16a-methyl-20-oxo-4,6-pregnadieno-[3,2 cJpyrazole 21-mesylate.

To 180 mg. of N-acetyl-l1fi,17a,2l-trihydroxy-16a methyl-20-oxo-4,6-pregnadieno-[3,2-c1pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water, The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-l 1B,17a-dihy'droxy-21-iodo-16u-methyl-20- oxo-4,6-pregnadieno- [3 ,2-c] pyrazole.

The N-acetyl-l1B,17ot-dihydroxy-21-iodo 16a methyl- 20-oxo-4,6-pregnadiene-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with Water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-11,B,17adihydroxy-l6a-methyl-20-oxo 4,6 pregnadieno [3,2-0] pyrazole.

To a solution of 62 mg. of N-acetyl-11f3,17e,21-trihydroxy-20-oxo-4,6-pregnadieno-[3,2-clpyrazole 21-mesyllate in 1 ml. of freshly distilled anhydrous dimethyl- 28 formamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-17a,21-epoxy- 1lfl-hydroxy-l6a-methyl-20-oxo-4,6-pregnadieno [3,2-c] pyrazole and N-acetyl-21-fluoro-11f3,17ot-dihydroxy-16a methyl-ZO-oxo 4,6 pregnadieno [3,2-c]pyrazole, which compounds are separated by partition chromatography or by chromatography on silica gel.

A 500 mg. aliquot of the N-acetyl-21-fluo1'o-116,170- dihydroxy-l6a-methyl-20-oxo 4,6 pregnadieno [3,2-c] pyrazole is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give the 21-fluoro-11/3,17a-dihydr0xy-16et methyl 20 oxo 4,6? pregnadieno-[3,2-c]pyrazole.

In accordance with the above procedures, but starting with the 11B,17u,21-trihydroxy-6-methyl-4,6-pregnadiene- 3,20-dione in place of the 11B,17 x,21-trihydroxy-16w methyl-4,6-pregnadiene-3,20-dione, there are obtained as products the corresponding 11/i,17a,21 trihydroxy 6- methyl-20-oxo-4,6 pregnadieno [3,2-c]pyraz0le and the N-acyl-, the 21-acylate, and the N-acyl-21-acylate derivatives thereof in which the two acyl groups may be the same or different; the 1lfi,17a-dihydroxy-6-methy1-20-oxo- 4,6-pregnadieno-[3,2-c1pyrazole and the N-acyl derivatives thereof; and the 21-fiuoro-11,8,17a-dihydroxy-6- methyl-20-oxo-4,6-pregnat1ieno- [3,2-c1pyrazole and the N-acyl derivatives thereof.

Example 5 To a suspension of 10 g. of 9a,11fl-dichloro-17a,2l dihydroxy-4,6-pregnadiene-3,20-dione in 475 ml. of alco hol-free chloroform and 300 ml. of methylene chloride, cooled to about 5 C. in an ice bath, is added with constant stirring 189 ml. of cold, concentrated hydrochloric acid and then 189 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 2 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed with water, then with a 5% solution of sodium bicarbonate and again with water. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is flushed three times with methanol. Hot methanol is then added and the product is filtered and then crystallized from a mixture of methylene chloride and u-hexane to give 17a,20,20,21-bis(methylenedioxy)-9oc,11fi-dichloro- 4,6-pregnadiene-3-one.

The 17a,20,20,21-bis(methylenedioxy)-9a,11p-dichloro- 4,6-pregnadiene-3-one (500 mg.) is suspended in 8.5 cc. of dry benzene and treated with 0.15 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 225 mg. of sodium hydride (as a 58% dispersion in mineral oil is added). The system is again evacuated and filled with nitrogen. The mixture is stirred under nitrogen for /2 hour after which time 0.2 ml. of ethyl formate is added and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crudeproduct which is dissolved in ether and purified as a sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether. The combined or- 27 ganic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,2l-bis(methylenedioxy)-9a,11fi-dichloro-2 hydro-xymethylene 4,6 pregnadiene-3-one.

The l7a,20,20,21-bis(methylenedioxy)-9a,1l e-dichloro-2-hydroxymethylene-4,6-pregnadiene-3-one (65 mg.) is dissolved in 0.7 ml. of absolute ethanol and treated with a solution of 0.12 ml. of hydrazine hydrate dissolved in 0.12 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and petroleum ether is added to give a solid which is 17a,20,20,2l-bis(methylenedioxy) -90c,1 1B-dichloro-4,6-pregnadieno-[3,2-c1pyrazole.

To a solution of 100 mg. of 17u,20,20,21-bis(methylenedioxy)-9 x,1lu-dichloro-4-,6 pregnadieno [3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of propionic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes,

the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold l N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-propionyl- 17a,20,20,21-bis(methylenedioxy)-9u,11J3 dichloro 4,6- pregnadieno-[3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of propionic anhydride, there is obtained the corresponding N-acyl-derivative.

The N-propionyl 17a,20,20,2l bis(methylenedioxy)- 9a,1lB-dichloro-4,6-pregnadieno-[3,2-c]pyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of N-propionyl- 9a,llfi-dichloro l7oc,2l dihydroxy--oxo-4,6-pregnadieno-[3,2-c]-pyrazole and N-propionyl-9a,1lfl-dichloro- 21 formyloxy 17oz hydroxy-20-oxo-4,6 pregnadieno- [3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 m1. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9oz,11;3-dichloro 17a,2l dihydroxy 20 oxo 4,6 pregnadieno- [3,2-c1pyrazole.

To a solution of 100 mg. of N-propi-onyl-9a,l1;8-dichloro 17,21 dihydroxy 20 oxo 4,6 pregnadieno- [3,2-c1-pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral. The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about C., in vacuo. The product is then crystallized from a solvent; alternately, the product may be chromatographed on alumina to give the N-propionyl-9a,11;8- dichloro 170:,21 dihydroxy-20-oxo 4,6 pregnadieno- [3,2-c]pyrazole 2l-acetate, which is isolated by crystallization of the appropriate eluate.

In accordance with the above procedure, but using an equivalent quantity of any other acylating agent in place of the acetic anhydride, there is obtained the corresponding N propionyl-9a,11 fl-dichloro 170:,21 dihydroxy-20- oxo-4,6-pregnadieno-[3,2-c]pyrazole 21-acylate.

In accordance with the above procedures, but starting with the 9oz,llB-dichloro 17o,21 dihydroxy-20-oxo-4,6- pregnadieno-[3,2-c]pyrazole and using two equivalents of another acylating agent there is obtained the corresponding N-acyl-Zl-acylate thereof.

A solution of 5.73 g. of N-propionyl-9a,1lB-dichloro- 1711,21 dihydroxy 20 oxo 4,6 pregnadieno-[3,2-c]- pyrazole 21-acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product aifords 9a,11;8-dichloro 17,21 dihydroxy 20 oxo 4,6 pregnadieno-[3,2-c]pyrazole ZI-acetate.

To a solution of mg. of N-propionyl-9a,11,B-dichloro 1704,21 dihydroxy 20 oxo 4,6 pregnadieno [3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-propionyl-9a,11fldichloro l7a,21 dihydroxy 20-oxo 4,6 pregnadieno- [3 ,2-c-] pyrazole 2 l-rnesylate.

To 180 mg. of N-propionyl-9a,11 8-dichloro-17a,21-di hydroxy 20 oxo 4,6 pregnadieno-[3,2-c]pyrazole 21- mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at refiux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-propionyl-9ot,1lfi-dichloro-17a-hydroxy-21-iodo- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give N-propionyl-9a,11fl-dichloro 170a hydroxy 21 iodo 20 oxo 4,6 pregna dieno-[3,2-c]pyrazole.

The N-propionyl-9a,1 1 p-dichloro- 1 7a-hydroxy-2 l-iodo- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-propionyl- 9ot,1lfi-dichloro-lh-hydroxy 20 oxo-4,6-pregnadieno- [3,2-c]pyrazole.

To a solution of 62 mg. of N-propionyl-9a,11fl-dichloro-l7ot,21-dihydroxy 20 oxo 4,6 pregnadieno- [3,2-c1pyrazole 21-rnesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is then added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-propionyl-9a,1l d-dichloro 17ot,21 epoxy-20- oxo-4,6-pregnadieno-[3,2-c]pyrazole and N-propionyllowed to stand overnight at room temperature.

water (until the aqueous layer is neutral).

arated by partition chromatography or by chromatography on silica gel.

A 500 mg. aliquot of the crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give N-propionyl- 9u,11/3-dichloro-21-fluoro-l7a-hydroxy oxo 4,6- pregnadieno-[3,2-c]pyrazole.

In accordance with the above procedures, but starting with the 900 bromo 11p chloro-17a,21-dihydroxy-4,6- pregnadiene-3,20-dione in place of the 9a,11;3-dichloro- 17a,21-dihydroxy-4,6-pregnadiene-3,20-dione there are obtained as products the corresponding 9ot-bromo-11fi chloro 170:,21 dihydroxy 20 oxo 4,6 pregnadieno- I [3,2-c]pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-Zl-acylate derivatives thereof in which the two .acyl groups may be the same or different; the 9a-bromo- 11,8-chloro 17oz hydroxy 20 oxo 4,6 pregnadieno- --[3,2-c]pyrazole and the N-acyl derivative thereof; and -the 4,6-pregnadieno-[3,2-c]p'yrazole and the N-acyl derivatives thereof.

The 9u,1l;8-dichloro 170:,21 dihydroxy-4,6-pregnadiene-3,20-dione and the 9a-bromo-11;8-chloro-l7a,21-dihydroxy-4,6-pregnadiene-3,20-dione compounds, as well as the substituted derivatives thereof (see columns 2 and 3), used as starting materials can be obtained in the following manner, starting from the corresponding 17a,21-dihydroxy-4-pregnene-3,20-dione.

A solution of 400 mg. of 170:,21-dihydroxy-4-pregnene- 3,20-dione in 2.0 ml. dimethyl formamide, 0.8 ml. of pyridine and 0.4 ml. of methanesulfonyl chloride is allowed to stand at 75 C. for one hour. The mixture is cooled and water is added. The precipitate formed is filtered, washed with water, dried in air and purified by chromatography on alumina and elution with benzene. Crystallization gives 17a,21-dihydroxy-4,9(11)-pregnadi ene-3,20-dione.

To a solution of 100 mg. of 17cc,21-dihydroXy-4,9(11)- pregnadiene-3,20-dione in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is al- A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl .acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is l3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the 17a,21-dihydroxy-4,9(1l)-pregnadiene-3,20- dione 21-acetate which is isolated by the addition of water and filtration.

To a stirred, cooled (05 C.) solution of 17oc,21-dl hydroxy-4,9( 11)-pregnadiene-3,20-dione-2l-acetate (1.0 g.) and lithium chloride (4.0 g.) in glacial acetic acid (40 ml.) is added N-chlorosuccinimide (383 mg., 1.1 equivalent) followed immediately by an anhydrous solution of hydrogen chloride (104 mg.) in tetrahydrofuran (1.0 ml.). Stirring is continued at room temperature for 3 hours, and the reaction mixture is poured into water (400 ml.). The resulting mixture is filtered and the residue is washed with water, and dried to yield a crude product. Crystallization from acetone gives 9a,11,B-dichloro-17,21-dihydroxy-4-pregnene 3,20 dione 21- acetate.

A suspension of 90,1le-dichloro-17a,21-dihydroxy-4- pregnene-3,20-dione 21-acetate (1.0 g.) in 0.27 N methtracted with ethyl acetate.

30 anolic perchloric acid (70 ml.) is stirred at room temperature for 17 hours. The reaction mixture is then poured into water (200 ml.) and filtered. The residue is washed with water and dried, giving a crude product, which is crystallized from acetone to yield 9a,11fl-di chloro-17a,21-dihydroxy-4-pregnene-3,20-dione.

To a stirred, cooled (0-5 C.) solution of 170:,21-dihydroxy-4,9( 11)-pregnadiene-3,20-dione 21-acetate (1.0 g.) and lithium chloride (4.0 g.) in glacial acetic acid (40 ml.) is added N-bromoacetamide (395 mg.) followed immediately by an anhydrous solution of hydrogen chloride (104 mg.) in tetrahydrofuran (1.0 ml.). Stirring is continued at room temperature for 3 hours, and the reaction mixture is precipitated with water and filtered. The residue is washed with water, and dried to yield a crude product. Crystallization from acetone gives 9a-bromo-1le-chloro-17a,21-dihydroxy-4-pregnene- 3,20-dione 21-acetate.

A suspension of t-bIOI'llO-11I3-Ch1OI'O-17u,21-dlh'ydroxy-4-pregnene-3,20-dione 21-acetate (1.0 g.) in 0.27

N methanolic perchloric acid (70 ml.) is stirred at room I 11B-ch1oro-17a,21-dihydroxy-4-pregnene-3,20-dione.

To a solution of mg. of 9a,1113-diChlO1'0-17a,-2l dihydroxy-4-pregnene-3,20-dione compound in 2 m1. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to standovernight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is ex- The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the 911,11B-dichloro-17a,21-dihydroxy-4- pregnene-3,20-dione 21-acetate which is isolated by addition of water and filtration.

A suspension containing 300 mg. of 9a,11 3-dichloro- 17a,21-dihydroxy-4-pregnene-3,ZO-dione 21-acetate, 700 mg. of chloranil, 8.3 ml. of ethyl acetate and 1.7 ml. of acetic acid in refluxed for 17 hours under nitrogen. The reaction mixture is diluted with 40 ml. of ethyl acetate and filtered. The filtrate is washed sequentially With two 20 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 20 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several 20 ml. portions of ice water. The aqueous washes are re-extracted with 50 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentracted in vacuo. The crude material dissolved in benzene is chromatographed on 15 g. of acid washed alumina. Elution with chloroform: ether 2:8 affords 9a,11,8-dichloro-17a, 2l-dihydroxy-4,6-pregnadiene-3,10-dione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 9a,11fl dichloro 17 oc,21 dihydroxy 4,6 pregnadiene- 3,20-dione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 9a,11 3-dichloro-17a,21-dihydroxy-4,6-pregnadiene-3,20-dione.

Example 6 A 5 g. sample of 9a-fiuoro-116,17a,21-trihydroxy-16amethyl-4,6-pregnadiene-3,20-dione is dissolved in a mixture of 235 ml. of chloroform and ml. of methylene chloride, cooled in an ice bath with stirring and treated with 85 m1. of formaldehyde (37%). An equal volume (85 ml.) of cold concentrated hydrochloric acid is added from a funnel over a 5-minute interval with stirring and aqueous solution of sodium hydroxide. avoid emulsification, the aqueous alkali is gently poured seer, rss

cooling. The mixture is stirred at room temperature for four hours. The layers are separated and the organic layer is washed free of acid by washing three times with water and then with a solution of sodium bicarbonate. The organic layers are washed free of bicardonate, dried over magnesium sulfate and taken to dryness. The gummy residue is treated with enough hot methanol on a steam bath to eifect trituration, and the resulting crystalline solid is separated by filtering the mixture while hot. (The filtrate is set aside and may deposit additional product overnight.) The crude product is dried to constant weight and purified by chromatography. The product is partially dissolved in 250 ml. of hot chloroform and diluted with an equal volume of hot benzene to complete solution. After cooling, the mixture is adsorbed in 100 g. of basic alumina and eluted with benzene and chloroform to give 17a,20,20,21-bis(methylenedioxy)-9 x-fiuoro-16emethyl-l 1/3-hydroxy-4,6-pregnadiene-3-one.

The 17a,20,20,2l-bis(methylenedioxy)-9a-fluoro-16 xmethyl-11[3-hydroxy-4,6-pregnadiene-3-one (3.25 g.) is disoslved in 76 ml. of dry pryridine and added to a cold solution prepared by the cautious addition of 3.25 g. of chromium trioxide (in portions) to 34.7 ml. of cold pyridine. The mixture is allowed to stand at room temperature overnight. The mixture is poured into water and extracted three times with ethyl acetate, avoiding excessive shaking especially during the third extraction. The combined ethyl acetate extracts are washed three times with 1 N sulfuric acid and then with water until neutral. The combined ethyl acetate extracts are dried over magnesium sulfate and taken to dryness to give 2.94 g. of product. The product is dissolved in benzene, adsorbed on basic alumina and eluted with 8:2 benzenezchloroform to give 17oc,20,20,21 bis(methylenedioxy) 9a fluoro 16ccmethyl-4,6-pregnadiene-3,1l-dione.

A 2.60 g. sample of 17e,20,20,2l-bis(methylene-dioxy)- 9os-fluoro-l6a-rnethyl-4,6-pregnadiene-3,1l-dione is dissolved in 95 ml. of dry benzene using dry equipment and treated with 2.43 ml. of freshly distilled ethyl formate. About 1.19 g. of a dispersion of sodium hydride in mineral oil (about 51%) is added, followed by about 1.19 g. of freshly prepared dry sodium methoxide (dried at about 175 C. oil pump for 4 hours). The air in the system is again replaced with nitrogen and the mixture, which turns yellow at once, is stirred at room temperature for one and one-half hours. At this point the color of the reaction mixture is a dark orange. The mixture is chilled in an ice bath and a cold, saturated solution of sodium dihydrogen phosphate is added gradually to decompose excess sodium hydride and neutralize the sodium methoxide. Ether is added and the layers are separated. The aqueous layers are back-extracted with ether and the combined organic layers are washed free of acid with water and then extracted three to four times with a 5% aqueous solution of sodium bicarbonate. These extracts are set aside. The product is now extracted four to five times with a cold 2% (in order to into the separatory funnel and the layers are separated without shaking the funnel. The last two extracts may be shaken with care.) The dark liquor is back-extracted two times with ether, and finally acidified in the cold with saturated aqueous solution of sodium dihydrogen phosphate. The neutral ether-benzene fraction should be set aside and processed as described below. The product is extracted into ether, and the ether extracts are washed free of acid with a saturated solution of sodium chloride. After drying over magnesium sulfate, the ether solution is taken to dryness and the amorphous products is crystallized from methanol to give l7a,20,20,2l-bis(methylenedioxy) 9e fluoro 2 hydroxy methylene 16ccmethyl-4,6-pregnadiene-3,1l-dione. This material is satisfactory for use in the next step.

A 1.00 g. aliquot of l7rx,20,20,21-bis(methylenedioxy)- 9oc-fluoro-2-hydroxymethylene 160c methyl-4,6-pregnadiene-3,11-dione is suspended in 44 ml. of absolute ethanol and treated with 0.38 ml. of hydrazine hydrate (99- 100%). The air in the system is replaced with nitrogen and the mixture is quickly brought to the reflux temperature. After refluxing for one hour the mixture is taken to dryness; the residual oil is treated with water and the resulting amorphous solid is removed by filtration, washed thoroughly with water and dried. The yield is about 900 mg. The crude product is dissolved in absolute ethanol and concentrated in vacuo until the solid separates. The solid is redissolved by heating, and then allowed to crystallize slowly to afford 17a,20,20,21-bis(methylenedioxy)- 9a-fiuoro-16a-methyl-1l-oxo 4,6 pregnadieno-[3,2-c] pyrazole.

A 455 mg. aliquot of 17a,20,20,21-bis(methylenedioxy)-9a-fiuoro-l6oc-methyl 11 oxo 4,6 pregnadieno- [3,2-c]-pyrazole is suspended in 75 ml. of a solution of sodium borohydride in isopropanol which is prepared by suspending an excess of sodium borohydride in isopropanol, stirring vigorously for about 15 minutes, and filtering to separate the excess of sodium borohydride. To the suspension is added an 0.816 ml. aliquot of a solution of 0.55 ml. of triethylamine in 1.45 ml. of isopropanol. The mixture is stirred, and enough methylene chloride (about 30 ml.) is added, with cooling, to make the system homogeneous. One drop of water (ca 1/20 ml.) is added and the mixture is stirred in a nitrogen atmosphere at room temperature overnight. Insolubles generally separate out in the course of the reaction. The mixture is then cooled, and the excess of sodium borohydride is decomposed by the addition of cold 2.5 N hydrochloric acid. The mixture (pH ca 5) is taken to dryness in vacuo and the residue is washed with water and dried to give 170:,20, 20,21-bis(methylenedioxy) a fluoro-1 lB-hydroxy-lSamethyl-4,6-pregnadieno-[3,2-cl-pyrazole.

To a solution of mg. of 17u,20,20,21-bis(methylenedioxy)-9a-fiuoro-1Iii-hydroxy 16a methyl-4,6-pregnadieno-lj3,2-c]pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with water, ice-cold 1 N sulfuric acid until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate is then distilled at about 40 C. in vacuo to afford the N-acetyl-17m,20,20,21- bis(methylenedioxy) 9a-fluoro-1lfi-hydroxy-l6a-methyl- 4,6-pregnadieno-[3,2-c]-pyrazo1e which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N-acetyl-17a-20,20,2l-bis(methylenedioxy) 9ozfluoro-1lfi-hydroxy-16a-methyl-4,6-pregnadieno [3,2-c] pyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of N-acetyl-9oc-fluoro-11B,17c,21-trihydroxy-16u methyl 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole and N-acetyl-9ixfluoro-Zl-formyloxy 11,8,17u dihydroxy-16a-methyl-20 oxo-4,6-pregnadieno-[3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9a-fluoro-l1B,17a-21-trihydroxy-16a-methyl-20-oxo 4,6 pregnadieno [3,2-c] pyrazole.

To a solution of 100 mg. of N-acetyl-9a-fiuoro-116,1704, 2l-trihydroxy-l6a-methyl 20 oxo-4,6-pregnadieno[3, 2-c[pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and Water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The N-acetyl-9afluor-1lfi,l7ot,21 trihydroxy 16oc-methy1-20-oxo-4,6- pregnadieno[3,2-c]pyrazole 2l-acetate is then isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acetyl-9a-fluoro-11fl,l7ot,21-trihydroxy 16a methyl- 20-oxo-4,6-pregnadieno-[3,2-c] pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 9ot-fluoro-11p,17a,21-trihydroxy-16a-methyl-20- oxo-4,6-pregnadieno-[3,2-c1pyrazole and using two milliequivalents of another acylating agent, there is obtained the corresponding N-acyl-Zl-acylate thereof.

A solution of 5.73 g. of N-acyl-9ot-fluoro-11fl,17a,21- trihydroxy 16a. methyl 20 0x0 4,6 pregnadieno- [3,2-c]pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is Washed with Water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords 9oz-fitlOI'0-1 1,8,17ot,21- trihydroxy 160a methyl 20 oxo 4,6 pregnadieno- [3,2-c1pyrazole 21-acetate.

To a'solution of 85 mg. of N-acetyl-9a-fluoro-1l13, 17tx,2l trihydroxy 16a methyl 20 0x0 4,6 pregnadieno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl- 90c fiuoro ll/3,l7oc,21 trihydroxy 16a methyl 20- oxo-4,6-pregnadieno-[3,2-c]pyrazole 21 mesylate.

To 180 mg. of N-acetyl-9ot-fluoro-115,17ot,21-trihydroxy 16cc methyl 20 oxo 4,6 pregnadieno- [3,2-c]pyrazole 21-rnesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, Washed with Water, and dried to give N-acetyl-9ot-fluoro- 11 8,17 dihydroxy 21 iodo 16a methyl 20 0x0- 4,6-pregnadieno- [3,2-c] pyrazole.

The N-acetyl-9ot-fiuoro-11 B,17ot-dihydroxy 21 iodo- 16a-methyl-20-oxo-4,G-pregnadieno [3,2 c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hr. The reaction solution is cooled, diluted with water, the material which separates is recovered by filtration. The product is Washed with water, dried and recrystallized from ethyl acetate to give N acetyl 90 fluoro 1113,17oc dihydroxy 16a methyl-ZO-oxo-4,6-pregnadieno-[3,2-c1pyrazole.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9afiuoro 115,17 dihydroxy 16oz methyl 20 oxo- 4,6-pregnadieno-[3,2-c]pyrazole.

To a solution of 62 mg. of N-acetyl-9u-fluoro-1 1B, 17 t,2l trihydroxy 16a methyl 20 oxo 4,6 pregnadieno-[3,2-cJpyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethyl-formamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N acetyl 1766,21 epoxy-9a-fluoro-l1 3-hydroxy 16a methyl 20 oxo 4,6 pregnadieno- [3,2-c]pyrazole and N-acetyl-9ot,21-difiuoro-1lB,17ot-dihydroxy 16a methyl 20 oxo 4,6 pregnadieno- [3,2-c]pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant Weight to give 9:1,21- difluoro 1704,21 dihydroxy 16a methyl 20 0x0- 4,6 pregnadieno- [3 ,2-c] pyrazole.

In accordance with the above procedures, but starting with the 9a-fiuOI0-1 1,8,17a,2l-trihydroxy-16-methylene- 4,6-pregnadiene-3,20-dione in place of the 9ot-fluoro-11B, 17ot,21 trihydroxy 16a methyl 4,6 pregnadiene- 3,20-dione, there are obtained as products the corresponding c fluoro 1lt3,l7oc,2l trihydroxy 16- methylene 11,20 dioxo 4,6 pregnadieno [3,2 c]- pyrazole and the N-acyl-, and 21-acylate, and the N-acyl- 21-acylate derivatives thereof in which the two acyl groups may be the same or difierent; the 9a-fiuoro-17a, 21 dihydroxy 16 methylene 11,20 dioxo 4,6- pregnadieno-[3,2-c]pyrazole and the N-acyl derivative thereof, and the 9a,21-difiuoro-116,17a-dihydr0xy-l6- methylene 11,20 dioxo 4,6 pregnadieno [3,2 c]- pyrazole and the N-acyl derivatives thereof.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 90:,21- difluoro 17a,2l dihydroxy 16a methyl 20 oxo- 4,6-pregnadieno-[3,2-c]pyrazole.

Example 7 About 6 g. of 17a,20,20,21-bis(methylenedioxy)-11/3- hydroxy-16ot-methyl-4,6-pregnadiene-3-one (Example 4) is suspended in about 35 ml. of dry benzene, and to this suspension is added 6 ml. of ethyl formate and about 1 g. of freshly prepared sodium methoxide. The mixture is allowed to stand at room temperature under nitrogen for 1% hours and is then cooled in an ice bath. The mixture is then acidified with an excess of a saturated aqueous solution of potassium dihydrogen phosphate. Ether is added and the product is extracted several times with a 2% aqueous solution of sodium hydroxide. The extracts are back-extracted with ether which is acidified with cold 2.5 N HCl, and then extracted with methylene chloride. The methylene chloride extracts are washed with aqueous saturated Sodium chloride solution, dried over magnesium sulfate and then taken to dryness. The re sulting product is crystallized with etherzpetroleum ether to give 17a,20,20,2l-bis(methylenedioxy)-1lfi-formyloxy- 2-hydroxymethylene-16a-methyl-4,6-pregnadiene-3-one.

To 1.422 g. of 17e,20,20,21-bis(methylenedioxy)- 11,8 formyloxy 2 hydroxymethylene 1606-I11thyl'4,6- pregnadiene-3-one, suspended in 18 ml. of absolute ethanol, is added 0.45 ml. of phenylhydrazine. The reaction mixture is refluxed for 40 minutes under nitrogen and then cooled. The 17a,20,20,21-bis (methylenedioxy)- llfi formyloxy 161x methyl-2-phenyl-4,6-pregnadieno- [3,2-c1pyrazole, which is formed as the major product, separates out and is recrystallized.

The 17a,2i),20,21-bis(methylenedioxy)-11fi-formyloxy- 16a methyl2-phenyl-4,o-pregnadieno-[3,2-c1pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give a solid which is a mixture of 11B,17ot,2l-trihydroxy-l6a-methyl-20-ox0-2C phenyl-4,6-pregnadieno-[3,2-c1pyrazole and l1fi,17a,2ltrihydroxy 16a methyl-20-oxo-2'-phenyl-4,6-pregnadieno-[3,2-c]pyrazole 21-formate.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with water, filtered and dried to constant weight to give 11l3,17ot,21- trihydroxy 16a methyl 20-oxo-2'-phenyl-4,6-pregnadieno-[3,2-c]PyraZole.

Example 8 To a solution of 0.5 millimole of 17a,20,20,21- bis(methylenedioxy) 11,8-hydroxy-2-hydroxymethylene- 16a-methyl-4,6-pregnadiene-3-one (Example 4) in about 3 ml. of absolute ethanol is added 0.6 millimole of sodium acetate and then 0.6 millimole of methylhydrazine sulfate. The mixture is refluxed under nitrogen for 40 minutes and then filtered hot. The filtrate is taken to dryness, water is added, and the 17a,20,20,21-bis(methylenedioxy) N,160t dimethyl-l lfi-hydroxy-4,6-pregnadicno- [3,2-c]pyrazole which is formed as the major component is removed by filtration.

Alternately, a mixture of 1',l6ot-dimethyl-, and 2,16adimethyl-17a,20,20,21-bis (methylenedioxy) -1 lfi-hydroxy- 4,6 pregnadieno [3,2-c1pyrazole is prepared by heating 17a,20,20,21 bis (methylenedioxy) 11B hydroxy-Z-hydroxymethylene- 160a methyl-4,6-pregnadiene-3-one with methanol in the presence of p-toluenesulfonic acid to form the 17a,20,20,21 bis(methylenedioxy) 11 8-hydroxy-2- methoxymethylene-16a-methyl-4,6-pregnadiene-3-one, and then reacting the latter compound with methylhydrazine, following the detailed procedures given in column 39, but using methylhydrazine instead of phenylhydrazine in the second step of the reaction. The components of the mixture are separated by chromatography.

In accordance with all the above procedures, but using other alkyl substituted hydrazines such as ethyl-, ,B-hydroxyethyl-, propyl-, butylhydrazines, and the like, in place of methylhydrazine, there are obtained the corresponding 1'-alkyland 2'-alkyl-17a,20,20,21-bis(methylenedioxy) 11,8 hydroxy- 16ot-methyl-4,6-pregnadieno- [3,2-c1pyrazoles.

Alternately the 170z,20,20,21 bis (methylenedioxy)- N,l6cc dimethyl 11,8 hydroxy-4,6-pregnadieno-[3,2-c]- pyrazoles may be prepared by the following procedure:

The 17ot,20,20,21-bis(methylenedioxy)-1 1,8-hydroxy-2- hydroxymethylene-16a-methyl-4,6-pregnadiene-3 one is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is Washed three times with cold water and the resulting amorphous solid is dried at C. for one hour in high vacuum to give 17u,20,20,21-bis(methylenedioxy)- 1 1 e-hydroxy-16a-methyl-4,6-pregnadieno-[3,2-c] pyrazole.

A solution of about 0.47 millimole of 17a,20,20,21- bis(methylenedioxy) 1lfi-hydroxy-l6a-methyl-4,6-pregnadieno-[3,2-c]pyrazole in 10 ml. of benzene is treated with about 3038 mg. of about 51% sodium hydride (in oil suspension). After the addition of 2-3 ml. of dimethylformamide (dried over calcium hydride) and 5 ml. of methyl iodide, the mixture is stirred at room temperature overnight. The product is filtered, washed with methylene chloride, and the filtrate and washings are taken to dryness. The residue is treated with water and the product is filtered to afford as a major component the 17a,20,20,21-bis(methylenedioxy)-1lfi-hydroxy N,16 1- dimethyl-4,6-pregnadieno-[3,2-c]pyrazole.

in accordance with the above procedure, but using an other alkylating agent, for example, ethyl iodide, propyl iodide and the like, in place of the methyl iodide, there is obtained the corresponding 2 N-alkyl-17a,20,20,21-bis- (methylenedioxy) 11,3 hydroxy 16ct-methyl-4,6-pregnadieno- [3 ,2-c] pyrazole.

The 17a,20,20,2l-bis(methylenedioxy)-1 l/i-hydroxy Z, 16a-dimethyl-4,6-pregnadieno-[3,2-c]pyrazole (15 mg.) is heated on a steam bath with 1 ml. of 60% formic acid for about 20 minutes and then filtered hot. The filtrate is taken to dryness, water is added, and a mixture of the llo,17a,2l-trihydroxy-2',16a-dimethyl 20 oxo-4,6-pregnadieno-[3,2-c]pyrazole and its 21-formate is recovered by filtration. A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant Weight to give l1B,l7a,2l-trihydroxy-2,16cxdirnethyl 20 oxo 4,6- pregnadieno [3,2-c] pyrazole.

To a solution of 100 mg. of 11fl,17a,2l-trihydroxy- 2',16ot dimethyl-20-oxo-4,o-pregnadieno-[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and Water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The 1 1B,17a,2l-trihydroxy-2,16a-dimethyl-20- oxo-4,6-pregnadieno-[3,2-c1pyrazole 21-acetate is then isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride there is obtained the corresponding 11 3,17a,21-trihydroxy-2,l6m-dimethyl 20 oxo-4,6-pregnadieno-[3,2-c]pyrazole 21- acylate.

To a solution of mg. of 11 3,17a,21-trihydroxy- 2',l6a-dimethyl-20-oxo-4,6-pregnadieno-[3,2 c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate 3? which forms is recovered by filtration, washed with water, and dried to give 11B,17 x,21-trihydroxy-2,-l6ot-dimethyl- 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole 2l-mesylate.

To 180 mg. of 1l5,17u,21-trihydroxy-2',16a-dirnetl1yl- 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole 21-mesylate dissolved in ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, Washed with water, and dried to give 115,170.- dihydroXy-21-iodo-2',lea-dimethyl 2O oXo 4,6 pregnadieno- 3,2-c] pyrazole.

The 11,8,17a-dihydroxy 21 iodo-2',16a-dimethyl-20- oxo-4,6-pregnadieno-[3,2-clpyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resul ing suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give 11B,17u-dihydroxy-2,16a-dimethyl 2O oxo-4,6-pregnadieno-[3,2-cl pyrazole.

To a solution of 62 mg. of 11/3,17 x,2l-trihydroxy- 2',16ct dimethyl--oxo-4,6-pregnadieno-[3,2-c1pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of 17a,21-epoxy- 1lfl-hydroxy-Z',16wdimethyl 20 oxo-4,6-pregnadieno- [3,2-c]pyrazole and 2l-fluoro-l1,8,l7a-dihydroxy-2,l6adimethyl-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures beginning with the 2'-methyl-17a,20,20,21-bis (methylenedioxy-l 1B- hydroxy-4,6-pregnadieno-[3,2-c1pyrazole, but using the 1'-methyl-derivative in place of the 2-methyl-derivative, there are obtained the corresponding 1-methyl-compounds.

In accordance with all of the above procedures, but starting with the 17a,20,20,2l-bis(methylenedioxy-Z-hydroxyrnethylene-4,6-pregnadiene-derivative which is obtained from each of the starting materials which are listed in columns 2 and 3, there are obtained the corresponding 1-methyland 2'-'nethyl derivative.

Example 9 To 200 mg. of l7u,20,20,2l-bis(methylenedioxy)-11,8- hydroxy-2-hydroxymethylene 16cc methyl-4,6-pregnadiene-3-one (Example 4) in 7 cc. of absolute ethanol is added 82 mg. of sodium acetate and then 102 g. of cyclohexylhydrazine oxalate. The mixture is refluxed under nitrogen for one hour. The insolubles are removed by filtration. The filtrate is taken to dryness. The residue is dissolved in 3 cc. of ether and the ether solution is washed successively with 2% aqueous sodium hydroxide and then with water to neutrality. The ether solution is then dried over magnesium sulfate, filtered and taken to dryness to give a residue which has as the major component the N cyclohexyl-17a,20,20,21-bis(methylenedioXy)-1ifi-hydroxy-16ot-methyl-4,6-pregnadieno-[3,2 c] pyrazole.

Alternately, a mixture of 1'-cyclohexyland 2'-cyclohexyl-17a,20,20,21-bis(methylenedioxy) 116 hydroxy- 4,6-pregnadieno-[3,2-c1pyrazole is prepared by heating 17a,20,20,21-bis(rnethylenedioxy) 11B hydroxy-Z-hydroxymethylene-l6a-methyl-4,6-pregnadiene-3-one with methanol in the presence of p-toluenesulfonic acid to form the 17a, 20,20,21-bis(methylened.ioxy) 115 hydroxy-2- methoxymethylene 16a methyl-4,6-pregnadiene-3-one, and then reacting the latter compound with cyclohexylhydrazine following the detailed procedures given in colunm 39, but using cyclohexylhydrazine instead of phenylhydrazine in the second step of the reaction. The components of the mixture are separated by chromatography.

A mg. aliquot of the N-CYClOhGXYl-17oc,20,20,21- bis (methylenedioxy) 11 3 hydroxy 16a methyl 4,6- pregnadieno-[3,2-c]pyrazole is heated under nitrogen with 5 cc. of a 60% aqueous solution of formic acid for about 40 minutes. The mixture is taken to dryness and Water is then added. The product is extracted with chloroform, and the chloroform solution is washed with saturated aqueous sodium chloride solution, 5% aqueous sodium bicarbonate solution and then with water. The chloroform solution is dried over magnesium sulfate and then taken to dryness to give a residue. This is taken up in ether containing a little methanol, stirred with 75 mg. of Darco G-6O (a decolorizing charcoal), filtered and taken to dryness to give N-cyclohexyl-l1B,17a,21-trihydroxy-16a-methyl-20-oxo-4,6-pregnadieno [3,2-c1pyrazole.

The 2'-cyclohexyl1 1e,17a,21-trihydroxy-l6a-methy1- 20-oxo-4,6-pregnadieno[3,2-c]pyrazole is converted into the 21-acetate, the 2-cyclohexyl-l1,8,17a-dihydroxy-16amethyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole, and into the 2'-cyclohexyl 21 fiuoro 116,170; dihydroxy-l6mmethyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole, following the detailed procedures given in Example 8 for the corresponding 2'-methyl-derivatives.

In accordance With the above procedures beginning with the 2-cyclohexyl-17u,20,20,2l-bis(methylenedioxy)- 11B hydroxy a methyl-4,6-pregnadieno-[3,2-c]pyrazole, but using the 1-cyclohexyl-derivative in place of the 2'-cyclohexyl-derivative, there are obtained the corresponding l-cyclohexyl-compounds.

In accordance with all of the above procedures, but starting with the 17a,20,20,21-bis(methylenedioXy)-2-hydroxymethylene-4,6-pregnadiene derivative which is obtained from each of the starting materials which are listed on pages 3-6, there are obtained the corresponding 1- cyclohexyland 2-cyclohexyl-derivatives.

In accordance with the above procedures, but using other cycloalkylhydrazines in place of cyclohexylhydrazine there are obtained the corresponding 1- and 2'-cycloalkyl derivatives.

Example 10 To a suspension of 25.0 g. of 1lfl,17a,21-trihydroxy 6,16a-climethyl-4,6-pregnadiene-3,20-dione in 1.5 l. of alcohol-free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is backextracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paper strip chromatography but shows two U.V. absorbing spots near the solvent front (methanolformamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,20,21-bis(methylenedioxy)-l1[$-hydroxy 6,160 dimethyl-4,6-pregnadiene-3- one which is used in the subsequent step of the synthesis without further purification.

17 a,20,20,21 bis (methylenedioxy) -l 1B-hydroxy-6, 1 6adimethyl-4,6-pregnadiene-3-one (500 mg.) is dissolved in 25 cc. of benzene and then about 5 cc. of benzene is ree9 moved by distillation at normal pressure. The resulting solution is cooled to room temperature. Then 0.75

cc. of freshly distilled ethyl formate is added. The air in the system is replaced with nitrogen and 150 mg. of sodium hydride (as a 57% dispersion in mineral oil) is added. The mixture is stirred under nitrogen at room temperature for three hours. Then cc. of a saturated aqueous solution sodium dihydrogen phosphate is added and the product is extracted into ether. The ether extracts are extracted with 2 N sodium hydroxide and the sodium hydroxide extracts are acidified with sodium dihydrogen phosphate and extracted again into ether. The ether extract is evaporated to dryness to give about 500 mg. of a crude product. From the ether solution there is obtained about 290 mg. of yellow crystals, MP. 220-236 C. which is \17a,20,20,21-bis(methylenedioxy)- llfl formyloxy 2 hydroxymethylene-6,lou-dimct' l- 4, 6-pregnadiene-3-one. The analytical sample is recrystallized from ethyl acetate and has a melting point of 249255 C., oc 217, LR. 5.81 ,a and 8.37 a. From the mother liquor is obtained about 127 mg. of 17a,20, 20,21-bis(methylenedioxy) 115 hydroxy 2 hydroxymethylene-6,16o-dimethyl 4,6 pregnadiene-S-one. The analytical sample is recrystallized from ether and has a melting point of 200-204 C., a -197, LR. 6.05-6.2 11., and 6.4 ,u.

The 17a,2O,20,21bis (methylenedioxy) -1 l ,B-hydroxy-Z- hydroxymethylene-6,16a-dirnethyl 4,6-pregnadiene-3-one (1.19 g.) is dissolved in cc. of ethanol. Three hundred mg. of phenyl hydrazine is added and the mixture is refluxed under nitrogen for one hour. About 25 cc. of water is added. The product is then extracted into 150 cc. of ether. The extracts are washed with 2 N HCl, with saturated sodium bicarbonate, water and saturated sodium chloride solution, and then dried over sodium sulfate and evaporated to dryness to give about 1.2 g. of crude prodnot. On crystallization from ether there is obtained as a major component the l7ot,20,20,21-bis(methylenedioxy)- 1lfl-hydroxy-6,l6u-dimethyl-2-phenyl 4,6 pregnadieno- [3,2-cjpyrazole.

Alternately, a mixture of the 1-phenyland 2'-phenyl- 17u,20,2O,21-biS (methylenedioxy)-1 1B-hydroxy-6,16a dirnethyl-4,6-pregnadieno[3,2-cjpyrazole is prepared by the following route: A mixture of 1 gram of 17a,20,20,21-bis- (methylenedi0xy)-11p hydroxy-Z-hydroxymethylene 6, 16u-dimethyl-4,6-pregnadiene-3-one, 200 ml. of methanol, and 200 mg. of p-toluenesulfonic acid is heated to reflux temperature and then allowed to stand at room temperature for one hour. The reaction mixture is then diluted with water and extratced with ethyl acetate. The ethyl acetate extract is washed two times With 2 N aqueous sodium hydroxide solution and then with water. The ethyl acetate extract is then dried and concentrated in vacuo. The 17a,20,20,21 -'bis(methylenedioxy)-11,8-hydroxy-Z-methyoxymethylene-6,16a-dimethyl-4,6 pregnadiene-3-one is obtained by direct crystallization or by chromatography on acid-washed alumina and elution with ether: chloroform mixtures.

A mixture of 500 mg. of 17a,20,20,21-bis(methylenedioxy) 115 hydroxy-Z-methyoxymethylene 6,16zx-di methyl-4,6-pregnadiene-3-one, 100 ml. of ethanol, and 1 ml. of phenylhydrazine is heated under nitrogen until dissolved, and then allowed to stand under nitrogen at room temperature over night. Acetic acid (2 ml.) is added and the mixture is allowed to stand for another 4 hours. The reaction mixture is then diluted With ethyl acetate, washed two times with 2 N sulfuric acid, two times with 2.5 N sodium hydroxide, and then two times with water. The ethyl acetate extract is then dried, concentrated, and chromatographed on acid-washed alumina. Elution with benzene affords a product which on recrystallization from a mixture of benzene and ethyl acetate affords the 17a, 20,20,21 bis(methylenedioxy) 11(3 hydroxy 6,16a dimethyl 1' phenyl 4,6-pregnadiene-[3,2-c1pyrazole. .Further elution with a mixture of 1:1 ether: petroleum ether and crystallization from benzene, affords the 17st, 20,20,21-bis(methylenedioxy)-11,8 hydroxy 6,16u dimethyl 2' phenyl 4,6 pregnadieno [3,2-c] pyrazole. 17a,20,20,21-bis(methylenedioxy)11B-hydroxy-6,16a dimethyl 2 phenyl 4,6 pregnadieno-[3,2,c]pyrazole (430 mg), is heated on a steam bath under nitrogen with 40 cc. of a 60% aqueous solution of formic acid for about 30 minutes. About 40 cc. of water is added and the mixture is then extracted into 200 cc. of chloroform. The chloroform solution is washed with water, saturated sodium bicarbonate solution and water, then dried over sodium sulfate and evaporated under vacuum to give about 430 mg. of crude product. This is dissolved in 60 cc.-of absolute methanol, and 0.1 equivalent of sodium methoxide in methanol is added. The mixture is stirred under nitrogen at room temperature for 15 minutes. It is then acidified with acetic acid and the solvent is removed under vacuum at room temperature. About 20 cc. of water is added and the product is extracted into 150 cc. of ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate and then with water. it is then dried over sodium sulfate and taken to dryness to give an amorphous solid.

The crude product obtained above is dried in high vacuum and then dissolved in 4 cc. of pyridine. About 3 cc. of acetic anhydride is added. The mixture is then heated on the steam bath for about 15 minutes and then evap0- rated to dryness in vacuo. About 20 cc. of Water is added- The product is then extracted into 150 cc. of ethyl acetate, washed with saturated sodium bicarbonate solution and Water, and dried over sodium sulfate. The solvent is removed in vacuo to give a residue which is crystallized from ethyl acetate-benzene to yield about 250 mg. of 115- 17a,2l-trihydroxy-6,l6ot-dimethyl-20-oxo-2' phenyl 4,6- pregnadieno-[3,2-c1pyrazole 21-acetate.

One hundred mg. of 11,8,17a,21 trihydroxy-6,16a-dimethyl-20-oxo-2'-phenyl-4,6-pregnadieno-[3,2-c] pyrazole ZI-acetate is dissolved in 10 cc. of absolute methanol, and 1.1 equivalents of sodium methoxide in methanol is added. The mixture is stirred at room temperature under nitrogen for 15 minutes. The product is acidified with acetic acid and then evaporated at room temperature under vacuum. The residue is then taken up in cc. of chloroform, washed with Water, saturated sodium bicarbonate solution, and water, and dried over sodium sulfate and evaporated to dryness to afford about 100 mg. of 115,17u, 2l-trihydroxy-6,16a-dimethyl-ZO-oxo-2-phenyl-4,6 pregnadieno-[3,2-c]pyrazole.

The crude 1l,8,17o-21-trihydroxy-6,16ar-dimethyl-20- oxo-2'-phenyl-4,6-pregnadieno-[3,2-c]pyrazole is dissolved in 1.2 cc. of dimethylformamide. The solution is cooled to 0 C. and 0.07 cc. of methane sulfonyl chloride is added. The mixture is kept at 0 C for about one hour, 3 cc. of water is added and the product is extracted into 100 cc. of chloroform, washed With water, dried over sodium sulfate and taken to dryness to afford the crude 11,8,1'7oc, 21-trihydroxy-6,16a-dimethyl-20-oxo 2 phenyl 4,6- pregnadieno- [3 ,2-c1pyrazole 21-mesylate.

The 11,8,17w21 trihydroxy-6,16a-dimethyl-20-oxo-2'- phenyl-4,6-pregnadieno-[3,2-c]pyrazole 21-mesylate is suspended in 5.5 cc. of acetone and 117 mg. of sodium iodide is added. The mixture is refluxed under nitrogen for about one hour. It is then cooled on ice. On the addition of water there is formed a white precipitate which is filtered off, Washed with water, and dried under vacuum to give the 11 3,17a-dihydroxy-21-iodo-6,16ot-dimethyl-20- oxo-2'-phenyl-4,6-pregnadieno-[3,2-c]pyrazole.

The above material is dissolved in 5 cc. of ethanol. Five hundred mg. of sodium bisulfite in 5 cc. of water is added, and the mixture is refluxed for one hour under nitrogen. Ten cc. of water is then added and the product is extracted into 100 cc. of chloroform, washed with water, dried over sodium sulfate and taken to dryness, to give about 100 mg. of residue which is purified by chromatography on silica gel. The 11,8,17u-dihydroxy-6J6a- 

2. A COMPOUND SELECTED FROM THE GROUP OF COMPOUNDS HAVING STRUCTURAL FORMULAS A AND B:
 3. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6-FLUORO-11B,17A,21-TRIHYDROXY-20-OXO-4,6 - PREGNADIENO(3,2-C)PYRAZOLE, AND THE N-LOWER HYDROCARBON CARBOXYLIC ACYL, THE 21-LOWER HYDROCARBON CARBOXYLIC ACYLATE AND THE N-LOWER HYDROCARBON CARBOXYLIC ACYL-21-LOWER HYDROCARBON CARBOXYLIC ACYLATE DERVATIVES THEREOF. 